Zygosity and Strands

Zygosity and Strands

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I am not a biology expert but I have done some homework on understanding alleles, chromosomes, dna in the human genome. Still baffled by a question though:

As I understand it at a particular locus for e.g. if a human has a A on one chromosome and a G on another that individual is considered Heterozygous at that locus because of the difference in the nucleotides (A/G in this case).

However, my question is. What about an individual that has an A on the 3' -> 5' strand (and hence a complement T on the 5'-> 3' strand) on one chromosome but T on the 3'-> 5' (and its complement on the other strand) on the other chromosome. Is this individual considered heterozygos or homozygous?

Basically my question boils down to does the "directionality" of the A-T pairing matter on both chromosomes?

I was thinking it should as only one strand can code for genes which the other doesn't so it should matter whether the A is on the (3'-5') or on the other strand…

Any advice would be great!

The directionality of the strands matters, because genes can be encoded on both strands of a chromosome (each strand can be read in 3'-5' direction by RNA polymerase). Therefore someone with the A-T case you described is also heterozygous.

In humans, eye color is an example of an inherited characteristic: an individual might inherit the "brown-eye trait" from one of the parents. [1] Inherited traits are controlled by genes and the complete set of genes within an organism's genome is called its genotype. [2]

The complete set of observable traits of the structure and behavior of an organism is called its phenotype. These traits arise from the interaction of its genotype with the environment. [3] As a result, many aspects of an organism's phenotype are not inherited. For example, suntanned skin comes from the interaction between a person's genotype and sunlight [4] thus, suntans are not passed on to people's children. However, some people tan more easily than others, due to differences in their genotype: [5] a striking example is people with the inherited trait of albinism, who do not tan at all and are very sensitive to sunburn. [6]

Heritable traits are known to be passed from one generation to the next via DNA, a molecule that encodes genetic information. [2] DNA is a long polymer that incorporates four types of bases, which are interchangeable. The Nucleic acid sequence (the sequence of bases along a particular DNA molecule) specifies the genetic information: this is comparable to a sequence of letters spelling out a passage of text. [7] Before a cell divides through mitosis, the DNA is copied, so that each of the resulting two cells will inherit the DNA sequence. A portion of a DNA molecule that specifies a single functional unit is called a gene different genes have different sequences of bases. Within cells, the long strands of DNA form condensed structures called chromosomes. Organisms inherit genetic material from their parents in the form of homologous chromosomes, containing a unique combination of DNA sequences that code for genes. The specific location of a DNA sequence within a chromosome is known as a locus. If the DNA sequence at a particular locus varies between individuals, the different forms of this sequence are called alleles. DNA sequences can change through mutations, producing new alleles. If a mutation occurs within a gene, the new allele may affect the trait that the gene controls, altering the phenotype of the organism. [8]

However, while this simple correspondence between an allele and a trait works in some cases, most traits are more complex and are controlled by multiple interacting genes within and among organisms. [9] [10] Developmental biologists suggest that complex interactions in genetic networks and communication among cells can lead to heritable variations that may underlie some of the mechanics in developmental plasticity and canalization. [11]

Recent findings have confirmed important examples of heritable changes that cannot be explained by direct agency of the DNA molecule. These phenomena are classed as epigenetic inheritance systems that are causally or independently evolving over genes. Research into modes and mechanisms of epigenetic inheritance is still in its scientific infancy, however, this area of research has attracted much recent activity as it broadens the scope of heritability and evolutionary biology in general. [12] DNA methylation marking chromatin, self-sustaining metabolic loops, gene silencing by RNA interference, and the three dimensional conformation of proteins (such as prions) are areas where epigenetic inheritance systems have been discovered at the organismic level. [13] [14] Heritability may also occur at even larger scales. For example, ecological inheritance through the process of niche construction is defined by the regular and repeated activities of organisms in their environment. This generates a legacy of effect that modifies and feeds back into the selection regime of subsequent generations. Descendants inherit genes plus environmental characteristics generated by the ecological actions of ancestors. [15] Other examples of heritability in evolution that are not under the direct control of genes include the inheritance of cultural traits, group heritability, and symbiogenesis. [16] [17] [18] These examples of heritability that operate above the gene are covered broadly under the title of multilevel or hierarchical selection, which has been a subject of intense debate in the history of evolutionary science. [17] [19]

When Charles Darwin proposed his theory of evolution in 1859, one of its major problems was the lack of an underlying mechanism for heredity. [20] Darwin believed in a mix of blending inheritance and the inheritance of acquired traits (pangenesis). Blending inheritance would lead to uniformity across populations in only a few generations and then would remove variation from a population on which natural selection could act. [21] This led to Darwin adopting some Lamarckian ideas in later editions of On the Origin of Species and his later biological works. [22] Darwin's primary approach to heredity was to outline how it appeared to work (noticing that traits that were not expressed explicitly in the parent at the time of reproduction could be inherited, that certain traits could be sex-linked, etc.) rather than suggesting mechanisms.

Darwin's initial model of heredity was adopted by, and then heavily modified by, his cousin Francis Galton, who laid the framework for the biometric school of heredity. [23] Galton found no evidence to support the aspects of Darwin's pangenesis model, which relied on acquired traits. [24]

The inheritance of acquired traits was shown to have little basis in the 1880s when August Weismann cut the tails off many generations of mice and found that their offspring continued to develop tails. [25]

Scientists in Antiquity had a variety of ideas about heredity: Theophrastus proposed that male flowers caused female flowers to ripen [26] Hippocrates speculated that "seeds" were produced by various body parts and transmitted to offspring at the time of conception [27] and Aristotle thought that male and female fluids mixed at conception. [28] Aeschylus, in 458 BC, proposed the male as the parent, with the female as a "nurse for the young life sown within her". [29]

Ancient understandings of heredity transitioned to two debated doctrines in the 18th century. The Doctrine of Epigenesis and the Doctrine of Preformation were two distinct views of the understanding of heredity. The Doctrine of Epigenesis, originated by Aristotle, claimed that an embryo continually develops. The modifications of the parent's traits are passed off to an embryo during its lifetime. The foundation of this doctrine was based on the theory of inheritance of acquired traits. In direct opposition, the Doctrine of Preformation claimed that "like generates like" where the germ would evolve to yield offspring similar to the parents. The Preformationist view believed procreation was an act of revealing what had been created long before. However, this was disputed by the creation of the cell theory in the 19th century, where the fundamental unit of life is the cell, and not some preformed parts of an organism. Various hereditary mechanisms, including blending inheritance were also envisaged without being properly tested or quantified, and were later disputed. Nevertheless, people were able to develop domestic breeds of animals as well as crops through artificial selection. The inheritance of acquired traits also formed a part of early Lamarckian ideas on evolution.

During the 18th century, Dutch microscopist Antonie van Leeuwenhoek (1632–1723) discovered "animalcules" in the sperm of humans and other animals. [30] Some scientists speculated they saw a "little man" (homunculus) inside each sperm. These scientists formed a school of thought known as the "spermists". They contended the only contributions of the female to the next generation were the womb in which the homunculus grew, and prenatal influences of the womb. [31] An opposing school of thought, the ovists, believed that the future human was in the egg, and that sperm merely stimulated the growth of the egg. Ovists thought women carried eggs containing boy and girl children, and that the gender of the offspring was determined well before conception. [32]

An early research initiative emerged in 1878 when Alpheus Hyatt led an investigation to study the laws of heredity through compiling data on family phenotypes (nose size, ear shape, etc.) and expression of pathological conditions and abnormal characteristics, particularly with respect to the age of appearance. One of the projects aims was to tabulate data to better understand why certain traits are consistently expressed while others are highly irregular. [33]

Gregor Mendel: father of genetics Edit

The idea of particulate inheritance of genes can be attributed to the Moravian [34] monk Gregor Mendel who published his work on pea plants in 1865. However, his work was not widely known and was rediscovered in 1901. It was initially assumed that Mendelian inheritance only accounted for large (qualitative) differences, such as those seen by Mendel in his pea plants – and the idea of additive effect of (quantitative) genes was not realised until R.A. Fisher's (1918) paper, "The Correlation Between Relatives on the Supposition of Mendelian Inheritance" Mendel's overall contribution gave scientists a useful overview that traits were inheritable. His pea plant demonstration became the foundation of the study of Mendelian Traits. These traits can be traced on a single locus. [35]

Modern development of genetics and heredity Edit

In the 1930s, work by Fisher and others resulted in a combination of Mendelian and biometric schools into the modern evolutionary synthesis. The modern synthesis bridged the gap between experimental geneticists and naturalists and between both and palaeontologists, stating that: [36] [37]

  1. All evolutionary phenomena can be explained in a way consistent with known genetic mechanisms and the observational evidence of naturalists.
  2. Evolution is gradual: small genetic changes, recombination ordered by natural selection. Discontinuities amongst species (or other taxa) are explained as originating gradually through geographical separation and extinction (not saltation). is overwhelmingly the main mechanism of change even slight advantages are important when continued. The object of selection is the phenotype in its surrounding environment. The role of genetic drift is equivocal though strongly supported initially by Dobzhansky, it was downgraded later as results from ecological genetics were obtained.
  3. The primacy of population thinking: the genetic diversity carried in natural populations is a key factor in evolution. The strength of natural selection in the wild was greater than expected the effect of ecological factors such as niche occupation and the significance of barriers to gene flow are all important.

The idea that speciation occurs after populations are reproductively isolated has been much debated. [38] In plants, polyploidy must be included in any view of speciation. Formulations such as 'evolution consists primarily of changes in the frequencies of alleles between one generation and another' were proposed rather later. The traditional view is that developmental biology ('evo-devo') played little part in the synthesis, but an account of Gavin de Beer's work by Stephen Jay Gould suggests he may be an exception. [39]

Almost all aspects of the synthesis have been challenged at times, with varying degrees of success. There is no doubt, however, that the synthesis was a great landmark in evolutionary biology. [40] It cleared up many confusions, and was directly responsible for stimulating a great deal of research in the post-World War II era.

Trofim Lysenko however caused a backlash of what is now called Lysenkoism in the Soviet Union when he emphasised Lamarckian ideas on the inheritance of acquired traits. This movement affected agricultural research and led to food shortages in the 1960s and seriously affected the USSR. [41]

There is growing evidence that there is transgenerational inheritance of epigenetic changes in humans [42] and other animals. [43]

Rapid Screening for the Zygosity of CRISPR Mutations

The development of CRISPR/Cas9 revolutionized researchers’ ability to edit the genome at will. However, the nature of CRISPR edits is not entirely controllable or predictable. This uncertainty is due to the mechanism by which the edits are integrated into the genome.

When CRISPR induces a double-stranded break (DSB) in DNA, the break is repaired via random one- or two-base pair (bp) indels through nonhomologous end joining (NHEJ). In diploid cells, these mutations can take on one of three zygosities: monoalleic, where only one allele is mutated diallelic heterozygous, where both alleles are mutated differently or diallelic homozygous, where both alleles are mutated identically.

These different outcomes require researchers to screen their cell lines for the desired zygosity of the mutation. Next-generation sequencing (NGS) is the gold standard for zygosity screening, but the process is costly and time-consuming, particularly if there are many cell lines that require screening.

This tutorial will introduce a new screening method that uses Accucleave™ T7 CE , a T7 endonuclease I (T7EI)-based heteroduplex cleavage assay that specifically screens out cell lines with undesired zygosity prior to NGS. The tutorial will also introduce new statistical models that aid in determining the zygosity of cell lines, thus providing a rapid screening step that reduces the number of cell lines that must undergo sequencing, saving time and money.

How the Assay Works

AccuCleave T7 CE screens zygosity by identifying and cleaving DNA mismatches between corresponding alleles. If the mutation is monoallelic, diallelic homozygous, or diallelic heterozygous, T7EI will cleave the resulting heteroduplex, yielding a predictable fragmentation pattern. The relative concentration of cleaved fragments can be used to estimate the zygosity of monoclonal diploid cell lines.

The assay will not cleave the homoduplexes formed when diallelic homozygous mutations occur, rendering them indistinguishable from wild-type (WT) cells. Therefore, following PCR amplification, but prior to heteroduplex formation, it is necessary to introduce WT DNA to the mutated DNA at a 50/50 ratio to accurately measure the occurrence of all three possible zygosities in each cell line (Figure 1).

Figure 1. A representation of the possible zygosities of a nonhomologous end joining (NHEJ)-induced mutation following a CRISPR edit in a diploid cell, and the resulting duplexes when this DNA is mixed in a 50/50 ratio with wild-type DNA. Also shown are the theoretical cleavage percentages following the application of AccuCleave T7CE to each sample.

The AccuCleave T7 CE Kit is used after a PCR-amplified DNA sample is denatured and reannealed to allow heteroduplex formation. First, samples are mixed with the T7EI master mix and incubated at 37°C for 30–60 minutes, which allows the endonuclease time to cleave heteroduplexes. Then, the mixture is diluted with Tris-EDTA and analyzed using the Fragment Analyzer CRISPR Discovery Gel Kit from Advanced Analytical Technologies. Finally, the percentage of cleaved duplexes is calculated using the CRISPR plugin for PROSize ® Data Analysis Software.

The percent cleaved is calculated by measuring the relative amount of cleaved versus noncleaved fragments following T7EI digestion. Equation 1 describes how the percent cleaved is calculated: CF1 = the concentration of one of the resultant fragments following cleavage CF2 = the concentration of the other resultant fragment and CA= the concentration of the initial, noncleaved amplicon. When one is working with pooled cell lines, the percent mutated can be calculated from the percent cleaved using Equation 2, allowing for mutation detection as low as 5% mutated.

For monoclonal diploid cell lines, the zygosity can be predicted from the percent cleaved. When WT DNA is mixed in a 50/50 ratio with monoallelic DNA, the amount of mutated alleles in the whole sample will be 25%. When DNA from a cell line with a diallelic heterozygous mutation is mixed with WT DNA, 25% of the strands will harbor mutation A, 25% will have mutation B, and 50% will be WT.

Finally, when WT DNA is mixed with an equal portion of diallelic homozygous DNA, 50% of the total DNA will have the mutation. Based on composition of each of these pools, the theoretical probabilities that heteroduplexes will form are, with respect to zygosity, 37.5% for cell lines with monoallelic mutations, 61.5% for cell lines with diallelic heterozygous mutations, and 50.0% for cell lines with diallelic homozygous mutations (Figure 1). These theoretical percentages serve as landmarks that allow researchers to derive the zygosity of a mutation in a particular cell line based on the T7EI cleavage frequency.

Equation 1 and 2

Assessing the Assay’s Validity

In a proof-of-method study, the AccuCleave T7 CE Kit was used to assess the zygosity of several model DNA strands, each containing a multitude of single-nucleotide polymorphisms and indels of varying lengths. 1 After PCR amplification, the DNA sequences were digested using the kit. The researchers tested the kit on amplicons of varying lengths, and found that only the 600-bp amplicon exhibited cleavage rates within 5% of the theoretical value of each zygosity (Figure 2).

In the 600-bp amplicon, the endonuclease was able to cleave all single-base mismatches along with 1-, 2-, and 10-bp indels within 5% of the expected theoretical cleavage frequency for each mutation (Figure 3). As all zygosities fell within 5% of their theoretical percent cleaved landmarks, there was no overlap for monoallelic, diallelic homozygous, and diallelic heterozygous mutations, making them easily distinguishable (Figure 2). This method was further confirmed in CRISPR-edited rice.

Figure 2. A comparison of cleavage percentage for different amplicon lengths. The 600-bp amplicon was cleaved at rates that were consistent with the theoretical cleavage percentages (that is, 37.5% for monallelic mutations, 50% for diallelic homozygous mutations, and 62.5% for diallelic heterozygous mutations).

Figure 3. A comparison of cleavage percentage for different mutation types. All mutations were cleaved at values consistent with the theoretical cleavage percentages (that is, 37.5% for monallelic mutations and 50% for diallelic homozygous mutations).

As CRISPR is used more in diploid cells, such as in induced human pluripotent stem cells and cells from rodent models, it will become increasingly critical to use an assay that can prescreen cell lines for zygosity and reduce the need to perform NGS. AccuCleave T7 CE , a T7EI-based heteroduplex cleavage assay, accurately and reliably cleaves heteroduplexes, and an analysis of the resulting cleaved fragments can be used to characterize the zygosity of mutations in the sample. This tool can help researchers identify cell lines with their desired mutation prior to NGS, saving them time and money, and streamlining their CRISPR workflows.

Glossary of genetics

This glossary of genetics is a list of definitions of terms and concepts commonly used in the study of genetics and related disciplines in biology, including molecular biology and evolutionary biology. [1] It is intended as introductory material for novices for more specific and technical detail, see the article corresponding to each term. For related terms, see Glossary of evolutionary biology.

Also rendered as three-prime end.

The end of a single strand of DNA or RNA at which the chain of nucleotides terminates at the third carbon atom in the furanose ring of deoxyribose or ribose (i.e. the terminus at which the 3' carbon is not attached to another nucleotide via a phosphodiester bond in vivo, the 3' carbon is often still bonded to a hydroxyl group). By convention, sequences and structures positioned nearer to the 3'-end relative to others are referred to as downstream . Contrast 5'-end .

Also rendered as five-prime cap.

A specially altered nucleotide attached to the 5'-end of some primary RNA transcripts as part of the set of post-transcriptional modifications which convert raw transcripts into mature RNA products. The precise structure of the 5' cap varies widely by organism in eukaryotes, the most basic cap consists of a methylated guanine nucleoside bonded to the triphosphate group that terminates the 5'-end of an RNA sequence. Among other functions, capping helps to regulate the export of mature RNAs from the nucleus , prevent their degradation by exonucleases , and promote translation in the cytoplasm. Mature mRNAs can also be decapped.

Also rendered as five-prime end.

The end of a single strand of DNA or RNA at which the chain of nucleotides terminates at the fifth carbon atom in the furanose ring of deoxyribose or ribose (i.e. the terminus at which the 5' carbon is not attached to another nucleotide via a phosphodiester bond in vivo, the 5' carbon is often still bonded to a phosphate group). By convention, sequences and structures positioned nearer to the 5'-end relative to others are referred to as upstream . Contrast 3'-end .

Abbreviated in shorthand with the letter A .

One of the four main nucleobases present in DNA and RNA . Adenine forms a base pair with thymine in DNA and with uracil in RNA. Any pair of organisms which are related genetically and both affected by the same trait . For example, two cousins who both have blue eyes are an affected relative pair since they are both affected by the allele that codes for blue eyes. One of multiple alternative versions of an individual gene , each of which is a viable DNA sequence occupying a given position, or locus , on a chromosome . For example, in humans, one allele of the eye-color gene produces blue eyes and another allele of the eye-color gene produces brown eyes. The relative frequency with which a particular allele of a given gene (as opposed to other alleles of the same gene) occurs at a particular locus in the members of a population more specifically, it is the proportion of all chromosomes within a population that carry a particular allele, expressed as a fraction or percentage. Allele frequency is distinct from genotype frequency , although they are related.

Also called a sex chromosome, heterochromosome, or idiochromosome.

Any chromosome that differs from an ordinary autosome in size, form, or behavior and which is responsible for determining the sex of an organism. In humans, the X chromosome and the Y chromosome are sex chromosomes.

Also called differential splicing or simply splicing.

A regulated phenomenon of eukaryotic gene expression in which specific exons or parts of exons from the same primary transcript are variably included within or removed from the final, mature messenger RNA transcript. A class of post-transcriptional modification , alternative splicing allows a single gene to code for multiple protein isoforms and greatly increases the diversity of proteins that can be produced by an individual genome . See also RNA splicing . An organic compound containing amine and carboxyl functional groups, as well as a side chain specific to each individual amino acid. Out of nearly 500 known amino acids, a set of 20 are coded for by the standard genetic code and incorporated in sequence as the building blocks of polypeptides and hence of proteins . The specific sequence of amino acids in the polypeptide chains that form a protein are ultimately responsible for determining the protein's structure and function. The stage of mitosis and meiosis that occurs after metaphase and before telophase , when the replicated chromosomes are segregated and each of the sister chromatids are moved to opposite sides of the cell. The condition of a cell or organism having an abnormal number of one or more specific individual chromosomes (but excluding abnormal numbers of complete sets of chromosomes, which instead is known as euploidy ). A phenomenon by which the symptoms of a genetic disorder become apparent (and often more severe) at an earlier age in affected individuals with each generation that inherits the disorder. A series of three consecutive nucleotides within a transfer RNA which complement the three nucleotides of a codon within an mRNA transcript. During translation , each tRNA recruited to the ribosome contains a single anticodon triplet that pairs with one or more complementary codons from the mRNA sequence, allowing each codon to specify a particular amino acid to be added to the growing peptide chain. Anticodons containing inosine in the first position are capable of pairing with more than one codon due to a phenomenon known as wobble base pairing . The orientation of two strands of a double-stranded nucleic acid (and more generally any pair of biopolymers) which are parallel to each other but with opposite directionality . For example, the two complementary strands of a DNA molecule run side-by-side but in opposite directions, with one strand oriented 5' -to- 3' and the other 3'-to-5'. See template strand . Any chromosome that is not an allosome and hence is not involved in the determination of the sex of an organism. Unlike the sex chromosomes, the autosomes in a diploid cell exist in pairs, with the members of each pair having the same structure, morphology, and genetic loci .

Also called testcrossing.

The breeding of a hybrid organism with one of its parents or an individual genetically similar to one of its parents, often intentionally as a type of selective breeding , with the aim of producing offspring with a genetic identity which is closer to that of the parent. The reproductive event and the resulting progeny are both referred to as a backcross, often abbreviated in genetics shorthand with the symbol BC. A pair of two nucleobases on complementary DNA or RNA strands which are bonded to each other by hydrogen bonds. The ability of consecutive base pairs to stack one upon another contributes to the long-chain double helix structures observed in both double-stranded DNA and double-stranded RNA molecules. A measure of the gene expression level of a gene or genes prior to a perturbation in an experiment, as in a negative control. Baseline expression may also refer to the expected or historical measure of expression for a gene.

Also abbreviated as CAAT box or CAT box.

The conversion of a cell from one tissue-specific cell type to another. This involves dedifferentiation to a pluripotent state an example is the conversion of mouse somatic cells to an undifferentiated embryonic state, which relies on the transcription factors Oct4, Sox2, Myc, and Klf4. [3]

Also called a map unit (m.u.).

A unit for measuring genetic linkage defined as the distance between chromosomal loci for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. Though it is not an actual measure of physical distance, it is used to infer the distance between two loci based on the apparent likelihood of a crossover occurring between them. The part of a chromosome that links a pair of sister chromatids . During mitosis , spindle fibers attach to the centromere via kinetochores. The presence of two or more populations of cells with distinct genotypes in an individual organism, known as a chimera, which has developed from the fusion of cells originating from separate zygotes each population of cells retains its own genome, such that the organism as a whole is a mixture of genetically non-identical issues. Genetic chimerism may be inherited (e.g. by the fusion of multiple embryos during pregnancy) or acquired after birth (e.g. by allogeneic transplantation of cells, tissues, or organs from a genetically non-identical donor) in plants, it can result from grafting or errors in cell division. It is similar to but distinct from mosaicism . One copy of a newly copied chromosome , which is joined to the original chromosome by a centromere . A complex of DNA , RNA , and protein found in eukaryotic cells that is the primary substance comprising chromosomes . Chromatin functions as a means of packaging very long DNA molecules into highly organized and densely compacted shapes, which prevents the strands from becoming tangled, reinforces the DNA during cell division, helps to prevent DNA damage, and plays an important role in regulating gene expression and DNA replication .

Also called crossing over.

The duplication of an entire chromosome , as opposed to a segment of a chromosome or an individual gene . A DNA molecule containing part or all of the genetic material of an organism. Chromosomes may be considered a sort of molecular "package" for carrying DNA within the nucleus of cells and, in most eukaryotes, are composed of long strands of DNA coiled with packaging proteins which bind to and condense the strands to prevent them from becoming an unmanageable tangle. Chromosomes are most easily distinguished and studied in their completely condensed forms, which only occur during cell division . Some simple organisms have only one chromosome made of circular DNA, while most eukaryotes have multiple chromosomes made of linear DNA. A mutation occurring within a cis-regulatory element (such as an operator ) which alters the functioning of a nearby gene or genes on the same strand of DNA. Cis-dominant mutations affect the expression of genes because they occur at sites that control transcription rather than within the genes themselves. Any region of non-coding DNA which regulates the transcription of nearby genes , typically by serving as a binding site for one or more transcription factors . Contrast trans-regulatory element . The branch of genetics based solely on observation of the visible results of reproductive acts, as opposed to that made possible by the modern techniques and methodologies of molecular biology. Contrast molecular genetics . The process of producing, either naturally or artificially, individual organisms or cells which are genetically identical to each other. Clones are the result of all forms of asexual reproduction, and cells that undergo mitosis produce daughter cells that are clones of the parent cell and of each other. Cloning may also refer to biotechnology methods which artificially create copies of organisms or cells, or, in molecular cloning , copies of DNA fragments or other molecules. A type of coregulator that increases the expression of one or more genes by binding to an activator .

Also sense strand, positive (+) sense strand, and nontemplate strand.

The strand of a double-stranded DNA molecule whose nucleotide sequence corresponds directly to that of the RNA transcript produced during transcription (except that thymine bases are substituted with uracil bases in the RNA molecule). Though it is not itself transcribed, the coding strand is by convention the strand used when displaying a DNA sequence because of the direct analogy between its sequence and the codons of the RNA product. Contrast template strand see also sense . A series of three consecutive nucleotides in a coding region of a nucleic acid sequence. Each of these triplets codes for a particular amino acid or stop signal during protein synthesis . DNA and RNA molecules are each written in a language using four "letters" (four different nucleobases ), but the language used to construct proteins includes 20 "letters" (20 different amino acids). Codons provide the key that allows these two languages to be translated into each other. In general, each codon corresponds to a single amino acid (or stop signal), and the full set of codons is called the genetic code . Any non-protein organic compound that is bound to an enzyme. Cofactors are required for the initiation of catalysis. A property of nucleic acid biopolymers whereby two polymeric chains (or "strands") aligned antiparallel to each other will tend to form base pairs consisting of hydrogen bonds between the individual nucleobases comprising each chain, with each of the four types of nucleobase pairing exclusively with one other type of nucleobase e.g. in double-stranded DNA molecules, A pairs only with T and C pairs only with G . Strands that are paired in such a way, and the bases themselves, are said to be complementary. The degree of complementarity between two strands strongly influences the stability of the duplex molecule certain sequences may also be internally complementary, which can result in a single strand binding to itself . Complementarity is fundamental to the mechanisms governing DNA replication , transcription , and DNA repair . DNA that is synthesized from a single-stranded RNA template (typically mRNA or miRNA ) in a reaction catalyzed by the enzyme reverse transcriptase . cDNA is produced both naturally by retroviruses and artificially in certain laboratory techniques, particularly molecular cloning . In bioinformatics, the term may also be used to refer to the sequence of an mRNA transcript expressed as its DNA coding strand counterpart (i.e. with thymine replacing uracil ). See quantitative trait . The controlled, inducible expression of a transgene , either in vitro or in vivo.

Also called a canonical sequence.

A calculated order of the most frequent residues (of either nucleotides or amino acids ) found at each position in a common sequence alignment and obtained by comparing multiple closely related sequence alignments. An interdisciplinary branch of population genetics which applies genetic methods and concepts in an effort to understand the dynamics of genes in populations, principally in order to avoid extinctions and to conserve and restore biodiversity. A nucleic acid or protein sequence that is highly similar or identical across many species or within a genome , indicating that it has remained relatively unchanged through a long period of evolutionary time. The continuous transcription of a gene , as opposed to facultative expression , in which a gene is only transcribed as needed. A gene that is transcribed continuously is called a constitutive gene. A continuous stretch of genomic DNA generated by assembling cloned fragments by means of their overlaps. [2] A phenomenon in which sections of a genome are repeated and the number of repeats varies between individuals in the population, usually as a result of duplication or deletion events that affect entire genes or sections of chromosomes. Copy-number variations play an important role in generating genetic variation within a population. A protein that works together with one or more transcription factors to regulate gene expression . A type of coregulator that reduces (represses) the expression of one or more genes by binding to and activating a repressor .

The breeding of purebred parents belonging to two different breeds, varieties, or populations, often intentionally as a type of selective breeding , with the aim of producing offspring which share traits of both parent lineages or which show heterosis . In animal breeding, the progeny of a cross between breeds of the same species is called a crossbreed, whereas the progeny of a cross between different species is called a hybrid . The branch of genetics that studies how chromosomes influence and relate to cell behavior and function, particularly during mitosis and meiosis .

Abbreviated in shorthand with the letter C .

One of the four main nucleobases present in DNA and RNA . Cytosine forms a base pair with guanine .

Denoted in shorthand with the symbol Δ.

A type of mutation in which one or more bases are removed from a nucleic acid sequence . A polymeric nucleic acid molecule composed of a series of deoxyribonucleotides which incorporate a set of four nucleobases : adenine ( A ), guanine ( G ), cytosine ( C ), and thymine ( T ). DNA is most often found in the form of a " double helix ", which consists of two paired complementary DNA molecules resembling a ladder that has been twisted. The "rungs" of the ladder are made of pairs of nucleobases .

Denoted in shorthand with the somatic number 2n.

(of a cell or organism) Having two homologous copies of each chromosome . Contrast haploid and polyploid . Any quantity used to measure the dissimilarity between the gene expression levels of different genes . [4] The process of compacting very long DNA molecules into densely packed, orderly configurations such as chromosomes , either in vivo or in vitro. A high-throughput technology used to measure expression levels of mRNA transcripts or to detect certain changes in the nucleotide sequence . It consists of an array of thousands of microscopic spots of DNA oligonucleotides , called features, each containing picomoles of a specific DNA sequence. This can be a short section of a gene or other DNA element that is used as a probe to hybridize a cDNA , cRNA or genomic DNA sample (called a target) under high-stringency conditions. Probe-target hybridization is usually detected and quantified by fluorescence-based detection of fluorophore-labeled targets. Any of a class of enzymes that synthesizes DNA molecules from individual deoxyribonucleotides . DNA polymerases are essential for DNA replication and usually work in pairs to create identical copies of the two strands of an original double-stranded molecule. They build long chains of DNA by adding nucleotides one at a time to the 3'-end of a DNA strand, usually relying on the template provided by the complementary strand to copy the nucleotide sequence faithfully. The collection of processes by which a cell identifies and corrects structural damage or mutations in the DNA molecules that encode its genome . The ability of a cell to repair its DNA is vital to the integrity of the genome and the normal functionality of the organism. The process by which a DNA molecule copies itself, producing two identical copies of one original DNA molecule. The process of determining, by any of a variety of different methods and technologies, the order of the bases in the long chain of nucleotides that constitutes a sequence of DNA . A relationship between the alleles of a gene in which one allele produces an effect on phenotype that overpowers or "masks" the contribution of another allele at the same locus the first allele and its associated phenotypic trait are said to be dominant, and the second allele and its associated trait are said to be recessive . Often, the dominant allele codes for a functional protein while its recessive counterpart does not. Dominance is not an inherent property of any allele or phenotype, but simply describes its relationship to one or more other alleles or phenotypes it is possible for one allele to be simultaneously dominant over a second allele, recessive to a third, and codominant to a fourth. In genetics shorthand, dominant alleles are often represented by a single uppercase letter (e.g. "A", in contrast to the recessive "a"). Any mechanism by which organisms neutralize the large difference in gene dosage caused by the presence of differing numbers of sex chromosomes in the different sexes, thereby equalizing the expression of sex-linked genes so that the members of each sex receive the same or similar amounts of the products of such genes. An example is X-inactivation in female mammals. Any DNA molecule that is composed of two antiparallel , complementary nucleotide polymers, or "strands", which are bonded together by hydrogen bonds between the complementary nucleobases . Though it is possible for DNA to exist as a single strand , it is generally more stable and more common in double-stranded form. In most cases, the complementary base pairing causes the twin strands to coil around each other in the shape of a double helix .

Also called repression or suppression.

Any process, natural or artificial, which decreases the level of gene expression of a certain gene . A gene which is observed to be expressed at relatively low levels (such as by detecting lower levels of its mRNA transcripts) in one sample compared to another sample is said to be downregulated. Contrast upregulation . Towards or closer to the 3'-end of a chain of nucleotides . Contrast upstream .

Also called an expression construct.

A type of vector , usually a plasmid or viral vector, designed specifically for the expression of a transgene insert in a target cell, rather than for some other purpose such as cloning . For a given genotype associated with a variable non-binary phenotype , the proportion of individuals with that genotype who show or express the phenotype to a specified extent, usually given as a percentage. Because of the many complex interactions that govern gene expression , the same allele may produce a wide variety of possible phenotypes of differing qualities or degrees in different individuals in such cases, both the phenotype and genotype may be said to show variable expressivity. Expressivity attempts to quantify the range of possible levels of phenotypic variation in a population of individuals expressing the phenotype of interest. Compare penetrance .

Also called extranuclear DNA or cytoplasmic DNA.

Any DNA that is not found in chromosomes or in the nucleus of a cell and hence is not genomic DNA . This may include the DNA contained in plasmids or organelles such as mitochondria or chloroplasts, or, in the broadest sense, DNA introduced by viral infection. Extrachromosomal DNA usually shows significant structural differences from nuclear DNA in the same organism.

Formerly known by the abbreviation MGED.

An organization that works with others "to develop standards for biological research data quality, annotation and exchange" as well as software tools that facilitate their use. [5]

Also Giemsa banding or G-banding.

A technique used in cytogenetics to produce a visible karyotype by staining the condensed chromosomes with Giemsa stain. The staining produces consistent and identifiable patterns of dark and light "bands" in regions of chromatin , which allows specific chromosomes to be easily distinguished. Any segment or set of segments of a nucleic acid molecule that contains the information necessary to produce a functional RNA transcript in a controlled manner. In living organisms, genes are often considered the fundamental units of heredity and are typically encoded in DNA . A particular gene can have multiple different versions, or alleles , and a single gene can result in a gene product that influences many different phenotypes . The number of copies of a particular gene present in a genome . Gene dosage directly influences the amount of gene product a cell is able to express, though a variety of controls have evolved which tightly regulate gene expression . Changes in gene dosage caused by mutations include copy-number variations .

Also called gene amplification.

A type of mutation defined as any duplication of a region of DNA that contains a gene . Compare chromosomal duplication . The process by which the information encoded in a gene is converted into a form useful for the cell. The first step is transcription , which produces a messenger RNA molecule complementary to the DNA molecule in which the gene is encoded. For protein-coding genes, the second step is translation , in which the messenger RNA is read by the ribosome to produce a protein . A database for gene expression managed by the National Center for Biotechnology Information. These high-throughput functional genomics data are derived from experimental data from chips and next-generation sequencing. [6] [7] Any of a variety of methods used to precisely identify the location of a particular gene within a DNA molecule (such as a chromosome) and/or the physical or linkage distances between it and other genes. The sum of all of the various alleles shared by the members of a single population. Any of the biochemical material resulting from the expression of a gene , most often interpreted as the functional mRNA transcript produced by transcription of the gene or the fully constructed protein produced by translation of the transcript. A measurement of the quantity of a given gene product that is detectable in a cell or tissue is sometimes used to infer how active the corresponding gene is. The broad range of mechanisms used by cells to increase or decrease the production or expression of specific gene products , such as RNA or proteins . Gene regulation increases an organism's versatility and adaptability by allowing its cells to express different gene products when required by changes in its environment. In multicellular organisms, the regulation of gene expression also drives cellular differentiation and morphogenesis in the embryo, enabling the creation of a diverse array of cell types from the same genome . Any mechanism of gene regulation which drastically reduces or completely prevents the expression of a particular gene. Gene silencing may occur naturally during either transcription or translation . Laboratory techniques often exploit natural silencing mechanisms to achieve gene knockdown . A high-throughput technology used to simultaneously inactivate, identify, and report the expression of a target gene in a mammalian genome by introducing an insertional mutation consisting of a promoterless reporter gene and/or a selectable genetic marker flanked by an upstream splice site and a downstream polyadenylated termination sequence. The co-occurrence within a population of one or more alleles or genotypes with a particular phenotypic trait more often than might be expected by chance alone such statistical correlation may be used to infer that the alleles or genotypes are responsible for producing the given phenotype. A set of rules by which information encoded within nucleic acids is translated into proteins by living cells. These rules define how sequences of nucleotide triplets called codons specify which amino acid will be added next during protein synthesis . The vast majority of living organisms use the same genetic code (sometimes referred to as the "standard" genetic code ) but variant codes do exist. The process of advising individuals or families who are affected by or at risk of developing genetic disorders in order to help them understand and adapt to the physiological, psychological, and familial implications of genetic contributions to disease. Genetic counseling integrates genetic testing , genetic genealogy , and genetic epidemiology . [8] A measure of the genetic divergence between species, populations within a species, or individuals, used especially in phylogenetics to express either the time elapsed since the existence of a common ancestor or the degree of differentiation in the DNA sequences comprising the genomes of each population or individual.

Sometimes used interchangeably with genetic variation .

The total number of genetic traits or characteristics in the genetic make-up of a population, species, or other group of organisms. It is often used as a measure of the adaptability of a group to changing environments. Genetic diversity is similar to, though distinct from, genetic variability .

Also called allelic drift or the Sewall Wright effect.

A change in the frequency with which an existing allele occurs in a population due to random variation in the distribution of alleles from one generation to the next. It is often interpreted as the role that random chance plays in determining whether a given allele becomes more or less common with each generation, regardless of the influence of natural selection. Genetic drift may cause certain alleles, even otherwise advantageous ones, to disappear completely from the gene pool , thereby reducing genetic variation , or it may cause initially rare alleles, even neutral or deleterious ones, to become much more frequent or even fixed .

Also called genetic modification or genetic manipulation.

The direct, deliberate manipulation of an organism's genetic material using any of a variety of biotechnology methods, including the insertion or removal of genes , the transfer of genes within and between species, the mutation of existing sequences, and the construction of novel sequences using artificial gene synthesis . Genetic engineering encompasses a broad set of technologies by which the genetic composition of individual cells, tissues, or entire organisms may be altered for various purposes, commonly in order to study the functions and expression of individual genes, to produce hormones, vaccines, and other drugs, and to create genetically modified organisms for use in research and agriculture. The use of genealogical DNA testing in combination with traditional genealogical methods to infer the level and type of genetic relationships between individuals, find ancestors, and construct family trees, genograms, or other genealogical charts.

Also called genetic draft or the hitchhiking effect.

A type of linked selection by which the positive selection of an allele undergoing a selective sweep causes alleles for different genes at nearby loci to change frequency as well, allowing them to "hitchhike" to fixation along with the positively selected allele. If selection at the first locus is strong enough, neutral or even slightly deleterious alleles within the same linkage group may undergo the same positive selection because the physical distance between the nearby loci is small enough that a recombination event is unlikely to occur between them. Genetic hitchhiking is often considered the opposite of background selection. A specific, easily identifiable, and usually highly polymorphic gene or other DNA sequence with a known location on a chromosome that can be used to identify the individual or species possessing it. Any reassortment or exchange of genetic material within an individual organism or between individuals of the same or different species, especially that which creates genetic variation . In the broadest sense, the term encompasses a diverse class of naturally occurring mechanisms by which nucleic acid sequences are copied or physically transferred into different genetic environments, including homologous recombination during meiosis or mitosis or as a normal part of DNA repair horizontal gene transfer events such as bacterial conjugation , viral transduction , or transformation or errors in DNA replication or cell division. Artificial recombination is central to many genetic engineering techniques which produce recombinant DNA . A graph that represents the regulatory complexity of gene expression . The vertices (nodes) are represented by various regulatory elements and gene products while the edges (links) are represented by their interactions. These network structures also represent functional relationships by approximating the rate at which genes are transcribed .

Also called DNA testing or genetic screening.

A broad class of various procedures used to identify features of an individual's particular chromosomes, genes, or proteins in order to determine parentage or ancestry, diagnose vulnerabilities to heritable diseases, or detect mutant alleles associated with increased risks of developing genetic disorders . Genetic testing is widely used in human medicine, agriculture, and biological research.

Sometimes used interchangeably with genetic variation .

The formation or the presence of individuals differing in genotype within a population or other group of organisms, as opposed to individuals with environmentally induced differences, which cause only temporary, non-heritable changes in phenotype . Barring other limitations, a population with high genetic variability has a greater potential for successful adaptation to changing environmental conditions than a population with low genetic variability. Genetic variability is similar to, though distinct from, genetic diversity .

Sometimes used interchangeably with genetic diversity and genetic variability .

The genetic differences both within and between populations, species, or other groups of organisms. It is often visualized as the variety of different alleles in the gene pools of different populations. Any organism whose genetic material has been altered using genetic engineering techniques, particularly in a way that does not occur naturally by mating or by natural genetic recombination . The field of biology that studies genes , genetic variation , and heredity in living organisms. The entire complement of genetic material contained within the chromosomes of an organism, organelle, or virus. The term is also used to refer to the collective set of genetic loci shared by every member of a population or species, regardless of the different alleles that may be present at these loci in different individuals. The total amount of DNA contained within one copy of a genome , typically measured by mass (in picograms or daltons) or by the total number of base pairs (in kilobases or megabases ). For diploid organisms, genome size is often used interchangeably with C-value .

Also called chromosomal DNA.

The DNA contained in chromosomes , as opposed to the extrachromosomal DNA contained in separate structures such as plasmids or organelles such as mitochondria or chloroplasts. An epigenetic phenomenon that causes genes to be expressed in a manner dependent upon the particular parent from which the gene was inherited. It occurs when epigenetic marks such as DNA or histone methylation are established or "imprinted" in the germ cells of a parent organism and subsequently maintained through cell divisions in the somatic cells of the organism's progeny as a result, a gene in the progeny that was inherited from the father may be expressed differently than another copy of the same gene that was inherited from the mother. An interdisciplinary field that studies the structure, function, evolution, mapping, and editing of entire genomes , as opposed to individual genes . The ability of certain chemical agents to cause damage to genetic material within a living cell (e.g. through single- or double-stranded breaks, crosslinking , or point mutations ), which may or may not result in a permanent mutation . Though all mutagens are genotoxic, not all genotoxic compounds are mutagenic. The entire complement of alleles present in a particular individual's genome , which gives rise to the individual's phenotype . The process of determining differences in the genotype of an individual by examining the DNA sequences in the individual's genome using bioassays and comparing them to another individual's sequences or a reference sequence. Any biological cell that gives rise to the gametes of an organism that reproduces sexually. Germ cells are the vessels for the genetic material which will ultimately be passed on to the organism's descendants and are usually distinguished from somatic cells , which are entirely separate from the germ line . 1. In multicellular organisms, the population of cells which are capable of passing on their genetic material to the organism's progeny and are therefore (at least theoretically) distinct from somatic cells . The cells of the germ line are called germ cells . 2. The lineage of germ cells, spanning many generations, that contains the genetic material which has been passed on to an individual from its ancestors.

Abbreviated in shorthand with the letter G .

One of the four main nucleobases present in DNA and RNA . Guanine forms a base pair with cytosine .

Also abbreviated GC-content.

The proportion of nitrogenous bases in a nucleic acid that are either guanine ( G ) or cytosine ( C ), typically expressed as a percentage. DNA and RNA molecules with higher GC-content are generally more thermostable than those with lower GC-content due to molecular interactions that occur during base stacking. [9]

Denoted in shorthand with the somatic number n.

(of a cell or organism) Having one copy of each chromosome , with each copy not being part of a pair. Contrast diploid and polyploid . A set of alleles in an individual organism that were inherited together from a single parent. In a diploid organism, having just one allele at a given genetic locus (where there would ordinarily be two). Hemizygosity may be observed when only one copy of a chromosome is present in a normally diploid cell or organism, or when a segment of a chromosome containing one copy of an allele is deleted , or when a gene is located on a sex chromosome in the heterogametic sex (in which the sex chromosomes do not exist in matching pairs) for example, in human males with normal chromosomes, almost all X-linked genes are said to be hemizygous because there is only one X chromosome and few of the same genes exist on the Y chromosome .

Also called inheritance.

The passing on of phenotypic traits from parents to their offspring, either through sexual or asexual reproduction. Offspring cells or organisms are said to inherit the genetic information of their parents. 1. The ability to be inherited . 2. A statistic used in quantitative genetics that estimates the proportion of variation within a given phenotypic trait that is due to genetic variation between individuals in a particular population. Heritability is estimated by comparing the individual phenotypes of closely related individuals in the population. See allosome . The expression of a foreign gene or any other DNA sequence within a host organism which does not naturally contain the same gene. Insertion of foreign transgenes into heterologous hosts using recombinant vectors is a common biotechnology method for studying gene structure and function.

Also called hybrid vigor and outbreeding enhancement.

In a diploid organism, having two different alleles at a given genetic locus . In genetics shorthand, heterozygous genotypes are represented by a pair of non-matching letters or symbols, often an uppercase letter (indicating a dominant allele) and a lowercase letter (indicating a recessive allele), such as "Aa" or "Bb". Contrast homozygous . Any of a class of highly alkaline proteins responsible for packaging nuclear DNA into structural units called nucleosomes in eukaryotic cells. Histones are the chief protein components of chromatin , where they associate into complexes which act as "spools" around which the linear DNA molecule winds. They play a major role in gene regulation and expression .

Also called homologs.

A set of two matching chromosomes , one maternal and one paternal, which pair up with each other inside the nucleus during meiosis . They have the same genes at the same loci , but may have different alleles . A type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical ("homologous") molecules of DNA , especially that which occurs between homologous chromosomes . The term may refer to the recombination that occurs as a part of any of a number of distinct cellular processes, most commonly DNA repair or chromosomal crossover during meiosis in eukaryotes and horizontal gene transfer in prokaryotes. Contrast nonhomologous recombination . In a diploid organism, having two identical alleles at a given genetic locus . In genetics shorthand, homozygous genotypes are represented by a pair of matching letters or symbols, such as "AA" or "aa". Contrast heterozygous . Any constitutive gene that is transcribed at a relatively constant level across many or all known conditions. Such a gene's products typically serve functions critical to the maintenance of the cell. It is generally assumed that their expression is unaffected by experimental conditions. The offspring that results from combining the qualities of two organisms of different genera, species, breeds, or varieties through sexual reproduction. Hybrids may occur naturally or artificially, as during selective breeding of domesticated animals and plants. Reproductive barriers typically prevent hybridization between distantly related organisms, or at least ensure that hybrid offspring are sterile, but fertile hybrids may result in speciation. 1. The process by which a hybrid organism is produced from two organisms of different genera, species, breeds, or varieties. 2. The process by which a single-stranded DNA or RNA preparation is added to an array surface, in solution, and potentially anneals to the complementary probe . Note that with respect to a gene expression assay, hybridization refers to a step in the experimental paradigm, while in molecular biology or genetics , the term refers to the chemical process.

Also called introgressive hybridization.

The movement of a gene from the gene pool of one population or species into that of another population by the repeated backcrossing of hybrids of the two populations with one of the parent populations. Introgression is a ubiquitous and important source of genetic variation in natural populations, but may also be practiced intentionally in the cultivation of domesticated plants and animals. Any nucleotide sequence within a gene that is removed by RNA splicing during post-transcriptional modification of the mRNA primary transcript and is therefore absent from the final mature mRNA. The term refers to both the sequence as it exists within a DNA molecule and to the corresponding sequence in RNA transcripts. Contrast exon . A type of abnormal chromosome in which the arms of the chromosome are mirror images of each other. Isochromosome formation is equivalent to simultaneous duplication and deletion events such that two copies of either the long arm or the short arm comprise the resulting chromosome.


Single-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code.

SNPs in the coding region are of two types: synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence, while nonsynonymous SNPs change the amino acid sequence of protein.

  • SNPs in non-coding regions can manifest in a higher risk of cancer, [11] and may affect mRNA structure and disease susceptibility. [12] Non-coding SNPs can also alter the level of expression of a gene, as an eQTL (expression quantitative trait locus).
  • SNPs in coding regions:
      by definition do not result in a change of amino acid in the protein, but still can affect its function in other ways. An example would be a seemingly silent mutation in the multidrug resistance gene 1 (MDR1), which codes for a cellular membrane pump that expels drugs from the cell, can slow down translation and allow the peptide chain to fold into an unusual conformation, causing the mutant pump to be less functional (in MDR1 protein e.g. C1236T polymorphism changes a GGC codon to GGT at amino acid position 412 of the polypeptide (both encode glycine) and the C3435T polymorphism changes ATC to ATT at position 1145 (both encode isoleucine)). [13] :
        – single change in the base results in change in amino acid of protein and its malfunction which leads to disease (e.g. c.1580G>T SNP in LMNA gene – position 1580 (nt) in the DNA sequence (CGT codon) causing the guanine to be replaced with the thymine, yielding CTT codon in the DNA sequence, results at the protein level in the replacement of the arginine by the leucine in the position 527, [14] at the phenotype level this manifests in overlapping mandibuloacral dysplasia and progeria syndrome) – point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribedmRNA, and in a truncated, incomplete, and usually nonfunctional protein product (e.g. Cystic fibrosis caused by the G542X mutation in the cystic fibrosis transmembrane conductance regulator gene). [15]
  • SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of noncoding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and may be upstream or downstream from the gene.

    More than 335 million SNPs have been found across humans from multiple populations. A typical genome differs from the reference human genome at 4 to 5 million sites, most of which (more than 99.9%) consist of SNPs and short indels. [16]

    Within a genome Edit

    The genomic distribution of SNPs is not homogenous SNPs occur in non-coding regions more frequently than in coding regions or, in general, where natural selection is acting and "fixing" the allele (eliminating other variants) of the SNP that constitutes the most favorable genetic adaptation. [17] Other factors, like genetic recombination and mutation rate, can also determine SNP density. [18]

    SNP density can be predicted by the presence of microsatellites: AT microsatellites in particular are potent predictors of SNP density, with long (AT)(n) repeat tracts tending to be found in regions of significantly reduced SNP density and low GC content. [19]

    Within a population Edit

    There are variations between human populations, so a SNP allele that is common in one geographical or ethnic group may be much rarer in another. However, this pattern of variation is relatively rare in a global sample of 67.3 million SNPs, the Human Genome Diversity Project

    found no such private variants that are fixed in a given continent or major region. The highest frequencies are reached by a few tens of variants present at >70% (and a few thousands at >50%) in Africa, the Americas, and Oceania. By contrast, the highest frequency variants private to Europe, East Asia, the Middle East, or Central and South Asia reach just 10 to 30%. [20]

    Within a population, SNPs can be assigned a minor allele frequency—the lowest allele frequency at a locus that is observed in a particular population. [21] This is simply the lesser of the two allele frequencies for single-nucleotide polymorphisms.

    With this knowledge scientists have developed new methods in analyzing population structures in less studied species. [22] [23] [24] By using pooling techniques the cost of the analysis is significantly lowered. [ citation needed ] These techniques are based on sequencing a population in a pooled sample instead of sequencing every individual within the population by itself. With new bioinformatics tools there is a possibility of investigating population structure, gene flow and gene migration by observing the allele frequencies within the entire population. With these protocols there is a possibility in combining the advantages of SNPs with micro satellite markers. [25] [26] However, there are information lost in the process such as linkage disequilibrium and zygosity information.

      can determine whether a genetic variant is associated with a disease or trait. [27]
    • A tag SNP is a representative single-nucleotide polymorphism in a region of the genome with high linkage disequilibrium (the non-random association of alleles at two or more loci). Tag SNPs are useful in whole-genome SNP association studies, in which hundreds of thousands of SNPs across the entire genome are genotyped. mapping: sets of alleles or DNA sequences can be clustered so that a single SNP can identify many linked SNPs. (LD), a term used in population genetics, indicates non-random association of alleles at two or more loci, not necessarily on the same chromosome. It refers to the phenomenon that SNP allele or DNA sequence that are close together in the genome tend to be inherited together. LD can be affected by two parameters (among other factors, such as population stratification): 1) The distance between the SNPs [the larger the distance, the lower the LD]. 2) Recombination rate [the lower the recombination rate, the higher the LD]. [28]

    Importance Edit

    Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, chemicals, drugs, vaccines, and other agents. SNPs are also critical for personalized medicine. [29] Examples include biomedical research, forensics, pharmacogenetics, and disease causation, as outlined below.

    Clinical research Edit

    SNPs' greatest importance in clinical research is for comparing regions of the genome between cohorts (such as with matched cohorts with and without a disease) in genome-wide association studies. SNPs have been used in genome-wide association studies as high-resolution markers in gene mapping related to diseases or normal traits. [30] SNPs without an observable impact on the phenotype (so called silent mutations) are still useful as genetic markers in genome-wide association studies, because of their quantity and the stable inheritance over generations. [31]

    Forensics Edit

    SNPs have historically been used to match a forensic DNA sample to a suspect but has been made obsolete due to advancing STR-based DNA fingerprinting techniques. However, the development of next-generation-sequencing (NGS) technology may allow for more opportunities for the use of SNPs in phenotypic clues such as ethnicity, hair color, and eye color with a good probability of a match. This can additionally be applied to increase the accuracy of facial reconstructions by providing information that may otherwise be unknown, and this information can be used to help identify suspects even without a STR DNA profile match.

    Some cons to using SNPs versus STRs is that SNPs yield less information than STRs, and therefore more SNPs are needed for analysis before a profile of a suspect is able to be created. Additionally, SNPs heavily rely on the presence of a database for comparative analysis of samples. However, in instances with degraded or small volume samples, SNP techniques are an excellent alternative to STR methods. SNPs (as opposed to STRs) have an abundance of potential markers, can be fully automated, and a possible reduction of required fragment length to less than 100bp.[26]

    Pharmacogenetics Edit

    Some SNPs are associated with the metabolism of different drugs. [32] [33] SNP's can be mutations, such as deletions, which can inhibit or promote enzymatic activity such change in enzymatic activity can lead to decreased rates of drug metabolism [34] The association of a wide range of human diseases like cancer, infectious diseases (AIDS, leprosy, hepatitis, etc.) autoimmune, neuropsychiatric and many other diseases with different SNPs can be made as relevant pharmacogenomic targets for drug therapy. [35]

    Disease Edit

    A single SNP may cause a Mendelian disease, though for complex diseases, SNPs do not usually function individually, rather, they work in coordination with other SNPs to manifest a disease such as in Osteoporosis.[33] One of the earliest successes in this field was finding a single base mutation in the non-coding region of the APOC3 (apolipoprotein C3 gene) that associated with higher risks of hypertriglyceridemia and atherosclerosis.[34]. Some diseases caused by SNPs include rheumatoid arthritis, crohn’s disease, breast cancer, alzheimer's, and some autoimmune disorders. Large scale association studies have been performed to attempt to discover additional disease causing SNPs within a population , but a large number of them are still unknown.

      and rs6313 are SNPs in the Serotonin 5-HT2A receptor gene on human chromosome 13. [36]
    • A SNP in the F5 gene causes Factor V Leiden thrombophilia.[37] is an example of a triallelic SNP in the CRP gene on human chromosome 1. [38] codes for PTC tasting ability, and contains 6 annotated SNPs. [39]
    • rs148649884 and rs138055828 in the FCN1 gene encoding M-ficolin crippled the ligand-binding capability of the recombinant M-ficolin. [40]
    • An intronic SNP in DNA mismatch repair gene PMS2 (rs1059060, Ser775Asn) is associated with increased spermDNA damage and risk of male infertility. [41]

    As there are for genes, bioinformatics databases exist for SNPs.

    • dbSNP is a SNP database from the National Center for Biotechnology Information (NCBI). As of June 8, 2015 [update] , dbSNP listed 149,735,377 SNPs in humans. [42][43]
    • Kaviar[44] is a compendium of SNPs from multiple data sources including dbSNP.
    • SNPedia is a wiki-style database supporting personal genome annotation, interpretation and analysis.
    • The OMIM database describes the association between polymorphisms and diseases (e.g., gives diseases in text form)
    • dbSAP – single amino-acid polymorphism database for protein variation detection [45]
    • The Human Gene Mutation Database provides gene mutations causing or associated with human inherited diseases and functional SNPs
    • The International HapMap Project, where researchers are identifying Tag SNPs to be able to determine the collection of haplotypes present in each subject. allows users to visually interrogate the actual summary-level association data in one or more genome-wide association studies.

    The International SNP Map working group mapped the sequence flanking each SNP by alignment to the genomic sequence of large-insert clones in Genebank. These alignments were converted to chromosomal coordinates that is shown in Table 1. [46] This list has greatly increased since, with, for instance, the Kaviar database now listing 162 million single nucleotide variants (SNVs).

    Chromosome Length(bp) All SNPs TSC SNPs
    Total SNPs kb per SNP Total SNPs kb per SNP
    1 214,066,000 129,931 1.65 75,166 2.85
    2 222,889,000 103,664 2.15 76,985 2.90
    3 186,938,000 93,140 2.01 63,669 2.94
    4 169,035,000 84,426 2.00 65,719 2.57
    5 170,954,000 117,882 1.45 63,545 2.69
    6 165,022,000 96,317 1.71 53,797 3.07
    7 149,414,000 71,752 2.08 42,327 3.53
    8 125,148,000 57,834 2.16 42,653 2.93
    9 107,440,000 62,013 1.73 43,020 2.50
    10 127,894,000 61,298 2.09 42,466 3.01
    11 129,193,000 84,663 1.53 47,621 2.71
    12 125,198,000 59,245 2.11 38,136 3.28
    13 93,711,000 53,093 1.77 35,745 2.62
    14 89,344,000 44,112 2.03 29,746 3.00
    15 73,467,000 37,814 1.94 26,524 2.77
    16 74,037,000 38,735 1.91 23,328 3.17
    17 73,367,000 34,621 2.12 19,396 3.78
    18 73,078,000 45,135 1.62 27,028 2.70
    19 56,044,000 25,676 2.18 11,185 5.01
    20 63,317,000 29,478 2.15 17,051 3.71
    21 33,824,000 20,916 1.62 9,103 3.72
    22 33,786,000 28,410 1.19 11,056 3.06
    X 131,245,000 34,842 3.77 20,400 6.43
    Y 21,753,000 4,193 5.19 1,784 12.19
    RefSeq 15,696,674 14,534 1.08
    Totals 2,710,164,000 1,419,190 1.91 887,450 3.05

    The nomenclature for SNPs include several variations for an individual SNP, while lacking a common consensus.

    The rs### standard is that which has been adopted by dbSNP and uses the prefix "rs", for "reference SNP", followed by a unique and arbitrary number. [47] SNPs are frequently referred to by their dbSNP rs number, as in the examples above.

    The Human Genome Variation Society (HGVS) uses a standard which conveys more information about the SNP. Examples are:

    • c.76A>T: "c." for coding region, followed by a number for the position of the nucleotide, followed by a one-letter abbreviation for the nucleotide (A, C, G, T or U), followed by a greater than sign (">") to indicate substitution, followed by the abbreviation of the nucleotide which replaces the former [48][49][50]
    • p.Ser123Arg: "p." for protein, followed by a three-letter abbreviation for the amino acid, followed by a number for the position of the amino acid, followed by the abbreviation of the amino acid which replaces the former. [51]

    SNPs can be easily assayed due to only containing two possible alleles and three possible genotypes involving the two alleles: homozygous A, homozygous B and heterozygous AB, leading to many possible techniques for analysis. Some include: DNA sequencing capillary electrophoresis mass spectrometry single-strand conformation polymorphism (SSCP) single base extension electrochemical analysis denaturating HPLC and gel electrophoresis restriction fragment length polymorphism and hybridization analysis.


    In this article, we propose a novel long-read-based SV detection approach, cuteSV. It enables the thorough analysis of the complex signatures of SVs implied by read alignments. Benchmark results demonstrate that cuteSV achieves good yields and performance simultaneously. Especially, it has good sensitivity to detect SVs, even with low coverage sequencing data, and it also has outstanding scaling performance which is suited to handle many large datasets. We believe that cuteSV has the potentials to cutting-edge genomics studies.

    Extended Data Figure 1 In vitro and in vivo characterization of the wild-type 7889SA human iPS cell line.

    a, Immunofluorescence staining of pluripotent stem cell markers. b, iPS cells possess a normal human male karyotype. c, Nanostring expression analysis of pluripotent stem cell genes in reprogrammed iPS cells compared to HUES9. d, In vivo differentiation and analysis of iPS-cell-derived teratoma containing tissues of all germ cell layers. Scale bars, 100 μm.

    Extended Data Figure 2 CRISPR/Cas-blocking mutations increase HDR accuracy by preventing re-editing, are incorporated in multiple rounds of re-editing and can also be applied to scarless editing using CORRECT.

    a, b, HDR reads from five unpooled templates containing intended pathogenic and CRISPR/Cas-blocking or non-blocking control mutations. Percentages of accurate HDR for reads containing blocking (B) or control (C) mutations at the APP (a) and PSEN1 (b) locus in HEK293 cells. Values represent mean ± s.e.m. (n = 3). ND, not detected. ***P < 0.001, **P < 0.01, one-way ANOVA. c, d, Proportion of next-generation sequencing reads containing putative single, double, or triple HDR events (left) for APP (c) and PSEN1 (d). Putative ‘double HDR’ examples of the most frequent reads that either contain a non-blocking control mutation C with an additional CRISPR/Cas-blocking mutation B, or do not contain C and have two different CRISPR/Cas-blocking mutations (middle). Reads that contain the non-blocking mutation (C+) are more frequently re-edited to incorporate a CRISPR/Cas-blocking mutation (‘double HDR’) than reads containing a blocking mutation B instead of the non-blocking mutation C (C−). See Fig. 1c for legend. To facilitate data analysis, all replicates were pooled to increase read numbers for rare events. e, f, Schematics depicting details of the two tested CORRECT approaches: in step 1 of re-guide (e), the APP Swe mutation was introduced together with a CRISPR/Cas-blocking guide RNA target mutation, which was then removed again in step 2 using a re-sgRNA specific for the mutated sequence and wild-type Cas9. In step 1 of re-Cas (f), the APP A673T mutation was introduced together with a CRISPR/Cas-blocking PAM-altering NGCG mutation, which was then removed in step 2 using the VRER Cas9 variant, which specifically detects the NGCG PAM. We chose to use the very active APP-sgRNA12 to test CORRECT by re-Cas, which was also used in Fig. 3c and 3d to generate APP Swe mutant lines. However, as the APP Swe mutation is located in the target sequence of this sgRNA, it may block re-editing by CRISPR/Cas and could therefore complicate the interpretation of results. We therefore decided to knock-in the protective APP A673T mutation 49 instead, which lies outside of the target sequence. In both cases, the blocking mutations were removed using a CORRECT ssODN repair template, which restored the original sequence at the site of the blocking mutation (which blocks further re-cutting in this step), but retained the intended APP mutation. Note that due to repeated editing, CORRECT may increase the probability of off-target effects, but presumably not the number of potential off-target sites, as the same (for re-Cas) or a very similar (for re-guide) guide RNAs are used in both editing steps.

    Extended Data Figure 3 Analysis of CRISPR/Cas9-induced indels in gene edited iPS cells and HEK293 cells.

    a, Plot depicting frequency of indels at each position around the targeted locus in all next-generation sequencing reads with editing events from the analysis shown in Fig. 1. Insertions are plotted at the location where they begin, and deletions are plotted across all deleted base positions (top). Histogram illustrating distribution of indel sizes (bottom). b, Indel position (top) and size (bottom) of indel-containing alleles from single-cell clones analysed in Extended Data Fig. 4a, b.

    Extended Data Figure 4 Heterozygous clones with HDR on one allele almost always contain indels on the non-HDR allele, and longer ssDNA or dsDNA HDR repair templates do not influence mutation incorporation probabilities related to cut-to-mutation distance.

    a, Sanger sequencing reads of both APP alleles of a single-cell clone with mono-allelic HDR (blue arrow). The non-HDR allele is altered by NHEJ in the guide RNA target sequence (orange arrow). b, Single-cell clones with HDR on one allele are mostly altered by NHEJ on the non-HDR allele (APP, n = 26 PSEN1, n = 34). c, Schematic describing the generation of large ssDNA and dsDNA HDR repair templates for the PSEN1 locus (see Methods for details). d, The monotonic relationship between incorporation of intended mutations (M) by HDR and cut-to-mutation distance is not altered by providing longer ssDNA and dsDNA templates (n = 2). Red dashed trend line shows previously determined 100-nt oligonucleotide scan result (from Fig. 2d) for comparison.

    Extended Data Figure 5 Mutation incorporation rates at various cut-to-mutation distances follow the distance effect, and mixed repair templates as a strategy to generate heterozygous iPS cell single-cell clones.

    a, b, Incorporation rate of APP and PSEN1 pathogenic mutations at increasing distance from the cut site targeted by three distinct sgRNA/ssODN pairs is governed by distance. Incorporation rates (solid dots represent mean ± s.e.m., note s.e.m. is too small to be visible, (n = 3)) match almost exactly the curves for each locus previously determined by oligonucleotide scan (dashed trend line ± s.d. of raw data from Fig. 2c, d). ***P < 0.001, one-way ANOVA. c, d, Mixed ssODN editing approach at the APP locus with blocking mutations in one (c) or both (d) ssODNs (top) zygosity quantification of single-cell clones (d, bottom left) and incorporation rates of CRISPR/Cas-blocking mutation B and pathogenic mutation M determined by next-generation sequencing analysis (d, bottom right). Note that for the M/B approach in c, both oligonucleotides are incorporated at equal levels, as they have similar blocking activities, whereas for the M+B/B approach in d, the M+B ssODN is preferentially incorporated, presumably due to a synergistic blocking effect of both M and B. For the clone quantification in Fig. 3d, the rate of wild-type clones was not assessed, because the silent mutation did not introduce a restriction site. However, given the

    50% ssODN incorporation rates determined by deep sequencing, about 25% of HDR clones are predicted to be wild type. e, Mixed ssODN editing approach at the PSEN1 M146V locus (top). Using an sgRNA with the smallest possible cut-to-mutation distance (PSEN1-sgRNA5), two ssODNs were provided, each containing the same silent PAM-altering CRISPR/Cas-blocking mutation B, but only one containing the pathogenic mutation M. Frequencies of pathogenic mutation genotypes in single-cell clones with bi-allelic HDR of B (bottom left) and incorporation rates of CRISPR/Cas-blocking and pathogenic mutations by next-generation sequencing (bottom right). Note that due to the 9 bp distance to the cleavage site, the incorporation of M is lower than 50% (as expected from the distance effect).

    Extended Data Figure 6 Characterization of iPS-cell-derived cortical neurons.

    a, b, Sanger sequencing reads of APP Swe and PSEN1 M146V gene edited iPS cell lines. ce, Immunofluorescence staining of markers for neural precursors at DIV10 (c), cortical neurons at DIV65 (d) and functional synapses at DIV65 (e). Scale bars 100 μm (c, d), 10 μm (e). f, Evoked action potentials recorded in a neuron current-clamped to −65 mV. g, Mean (±s.e.m.) resting membrane potential (Vrest), action potential threshold and action potential overshoot (DIV 71–85 n = 18). Properties of the largest action potential elicited in each cell were measured. h, Mean number of evoked action potentials increases with increasing stimulus strength. i, Spontaneous synaptic activity recorded in a neuron voltage-clamped to −70 mV. j, Mean (± s.e.m.) frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) (DIV 71–85 n = 8).

    Extended Data Figure 7 Possible mechanism underlying the distance effect for HDR-mediated mutation incorporation with CRISPR/Cas9.

    CRISPR/Cas9 causes a DSB at a genomic locus, which leads to variable size deletions or strand resections in different cells. Genomes with small deletions or resections are more common than large ones, which is reflected in the distribution of deleted bases after NHEJ (top left). During HDR, only the part of the repair template overlapping this deletion may be used, which results in fewer mutations incorporations more distal to the cleavage site (bottom left, data pooled for APP and PSEN1 from Fig. 2d).

    Extended Data Figure 8 Next-generation sequencing data analysis pipeline for HDR and indel detection.

    a, For all next-generation sequencing experiments, raw forward and reverse paired next-generation sequencing reads were first merged to obtain single high-quality reads (tool: PEAR), de-multiplexed to separate experiment-specific barcoded reads (seqtk) then filtered to remove low-quality reads. b, For experiments using pooled oligonucleotides containing CRISPR/Cas-blocking mutations (displayed in Fig. 1), reads were separated into wild-type (WT) and edited reads, which were then filtered to include only reads that had incorporated the pathogenic mutation (M+) (that is, containing a pathogenic and CRISPR/Cas-blocking mutation). To account for multiple HDR events after re-editing, reads were then separated into 32 unique categories covering every possible combination of CRISPR/Cas-blocking mutations. c, Reads were aligned (bwa mem) and accurate HDR (perfect alignment) or indel distribution was reported (bam-readcount, R). For analysis in Extended Data Fig. 2c, d, reads that had incorporated multiple CRISPR/Cas-blocking mutation were separately analysed. d, For the mutation incorporation analyses performed in all other figures reads were filtered for the expected sequence and counted.

    Genotype and variation [ edit | edit source ]

    The genotype is the part (DNA sequence) of the genetic makeup of a cell, and therefore of an organism or individual, which determines a specific characteristic (phenotype) of that cell/organism/individual. Genotype is one of three factors that determine phenotype, the other two being inherited epigenetic factors, and non-inherited environmental factors. DNA mutations which are acquired rather than inherited, such as cancer mutations, are not part of the individual's genotype hence, scientists and physicians sometimes talk for example about the (geno)type of a particular cancer, that is the genotype of the disease as distinct from the diseased.

    An example of how genotype determines a characteristic is petal color in a pea plant. The genotype of an organism is the inherited map it carries within its genetic code. The genetic constitution of an organism is referred to as its genotype, such as the letters Bb. (B - dominant genotype and b - recessive genotype). Zygosity is the degree of similarity of the alleles for a trait in an organism.

    Most eukaryotes have two matching sets of chromosomes that is, they are diploid. Diploid organisms have the same loci on each of their two sets of homologous chromosomes, except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal sex-determination system. If both alleles of a diploid organism are the same, the organism is homozygous at that locus. If they are different, the organism is heterozygous at that locus. If one allele is missing, it is hemizygous, and, if both alleles are missing, it is nullizygous.

    The DNA sequence of a gene often varies from one individual to another. Those variations are called alleles. While some genes have only one allele because there is low variation, others have only one allele because deviation from that allele can be harmful or fatal. But most genes have two or more alleles. The frequency of different alleles varies throughout the population. Some genes may have two alleles with equal distribution. For other genes, one allele may be common, and another allele may be rare. Sometimes, one allele is a disease-causing variation while the other allele is healthy. Sometimes, the different variations in the alleles make no difference at all in the function of the organism. In diploid organisms, one allele is inherited from the male parent and one from the female parent. Zygosity is a description of whether those two alleles have identical or different DNA sequences. In some cases the term "zygosity" is used in the context of a single chromosome.

    Types of Twins: Several Different Twin Types

    Identical twins are also referred to as monozygotic twins or one-egg twins. They are the result of a single egg, fertilized by a single sperm cell.

    Very early in development, the egg divides, resulting in two individuals with the same DNA. Even though they may look identical, they have their own unique traits. This is due to various growth conditions in the womb.

    About 25 percent of all identical twins may be mirror twins. They are a subset of identical twins and are identical twins with opposite features. These mirrors are reflections of each other which means that the left side of one twin, matches the right side of the other twin.

    They may possess matching or almost matching fingerprints and share the same DNA. Organs and birthmarks can be placed on opposite sides of their bodies and one twin may be right-handed, whereas the other is left-handed. They result from a late split of the fertilized egg.

    There are some patterns of identical twinning that are exceedingly rare: in extremely rare cases twins that stem from one egg have been born with opposite sexes. The probability of this is extremely small – multiples having different genders is universally accepted as a sound basis for a clinical determination, that multiples do not stem from one egg.

    Conjoined twins

    Conjoined twins are also referred to as siamese twins. Conjoined twins are identical twins whose bodies are joined together at birth. This occurs when the fertilized egg fails to separate completely because they split very late in development. Most conjoined twins are also mirror twins.

    There is a type of conjoined twin that is sometimes referred to as parasitic twin. The condition is called Twin Reversed Arterial Perfusion (TRAP). Parasitic twins develop asymmetrically, with a smaller, less formed twin dependent on the stronger, larger twin.

    A variation of parasitic twinning is a fetus in fetu, where an abnormally formed mass of cells grows inside the body of its identical twin. It survives during pregnancy, and even occasionally after birth, by tapping directly into the blood supply of the host twin.

    Fraternal twins / two-egg twins

    Fraternal twins are also referred to as dizygotic twins, non-identical twins or two-egged twins. They develop from two different eggs each is fertilized by separate sperm cells.

    They share approximately 50 percent of their genes, similar to any other siblings born at different times, who have the same biological mother and father. This means, that the chances of them looking alike are the same as the likelihood of any other siblings.

    They may look very much alike – or they may look very different. Fraternal twins can be either gender or a combination of boy and girl.

    There are some patterns of twinning that are exceedingly rare. In rare cases, a woman’s eggs are fertilized at different times with two or more acts of sexual intercourse. This is known as superfetation and occurs when a woman continues ovulating after becoming pregnant.

    There have also been instances of fraternal twins with different fathers. This occurs when a woman releases multiple eggs and has sexual relations with more than one partner.

    If an egg is fertilized by sperm from one man, and then another egg is fertilized by sperm from another man, the result is fraternal twins with different fathers.

    This phenomenon is termed heteropaternal superfecundation and these fraternal twins are genetically half-siblings and share approximately 25 percent of their DNA.

    Semi identical twins

    Semi identical twins are also referred to as polar body twins or half identical twins.

    Semi identical twins are types of twins, who share half their genes in common from the mother and the other half different from two separate sperm cells. This occurs when two sperm fertilize one egg, which then later splits.

    They share some features of identical twins and some features of fraternal twins. These twins will look very much alike but aren’t a 100 percent DNA match.

    An embryo created this way doesn’t usually survive, but a few cases are known.

    Mixed chromosome twins

    Mixed chromosome twins are also referred to as chimeras.

    In human biology, a chimera is an organism with at least two genetically distinct types of cells – or, in other words, someone meant to be a twin. But while in the mother’s womb, two fertilized eggs fuse, becoming one fetus that carries two distinct genetic codes – two separate strands of DNA.

    Some individuals have been identified to have more than one distinct red blood cell type and individuals have been born, who are both female and male.

    Author information

    These authors contributed equally: Mathias Girbig, Agata D. Misiaszek.


    European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany

    Mathias Girbig, Agata D. Misiaszek, Matthias K. Vorländer, Helga Grötsch, Florence Baudin & Christoph W. Müller

    Candidate for joint PhD degree from EMBL and Heidelberg University, Faculty of Biosciences, Heidelberg, Germany

    Mathias Girbig & Agata D. Misiaszek

    European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK

    Aleix Lafita & Alex Bateman

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    C.W.M. initiated and supervised the project. M.G. initiated the project carried out EM grid preparation, data collection and processing and model building and interpreted the structures. A.D.M. generated HEK293F cell lines via CRISPR–Cas9-mediated gene editing and purified proteins and analyzed Pol III mutations. M.K.V. assisted with structural model building, interpretation of the structures and advice for EM data processing. A.L. and A.B. performed the phylogenomic analysis. F.B. did the RNA extension and cleavage assays. H.G. performed cell culture work and advised and assisted with CRISPR–Cas9-mediated gene editing and protein purification. M.G., A.D.M. and C.W.M. wrote the manuscript with input from the other authors.

    Corresponding author


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    Watch the video: Zygosity and Chronicity: what effects this and what does this mean? (June 2022).


  1. Mariel

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  2. Durr

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  3. Kenji

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  4. Kijind

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