Human genetic variation is the genetic diversity of humans and represents the total amount of genetic characteristics observed within the human species. Genetic differences are observed between humans at both the individual and the population level. There may be multiple variants of any given gene in the human population (alleles), leading to polymorphism. Many genes are not polymorphic, meaning that only a single allele is present in the population: that allele is then said to be fixed. ^[1]

No two humans are genetically identical, even monozygotic twins, who develop from a single zygote, have infrequent genetic differences due to mutations occurring during development and gene copy number variation has been observed.^[2] Differences between individuals, even closely related individuals, are the key to techniques such as genetic fingerprinting. Alleles occur at different frequencies in different human populations, with populations that are more geographically and ancestrally remote tending to differ more.

Causes of differences between individuals include the exchange of genes during meiosis and various mutational events. There are at least two reasons why genetic variation exists between populations. Natural selection may confer an adaptive advantage to individuals in a specific environment if an allele provides a competitive advantage. Alleles under selection are likely to occur only in those geographic regions where they confer an advantage. The second main cause of genetic variation is due to the high degree of neutrality of most mutations. Most mutations do not appear to have any selective effect one way or the other on the organism. The main cause is genetic drift, this is the effect of random changes in the gene pool. In humans, founder effect and past small population size (increasing the likelihood of genetic drift) may have had an important influence in neutral differences between populations.

The theory that humans recently migrated out of Africa, is sometimes given as an example of this. It has been theorised that the migration out of Africa only represented a small fraction of the genetic variation in Africa and that this is a contributing cause of the observed lower levels of diversity in all indigenous humans outside of Africa. Generally, more recent neutral polymorphisms caused by mutation are likely to be relatively geographically localised and rare, while older polymorphisms are more likely to be shared by a wider range of human groups. The large majority of observed genetic variation occurs within a population in any geographic region and not between populations in different regions, although it is still usually possible to accurately identify the geographic origins of any individual's ancestors by genetic means.

The study of human genetic variation has both evolutionary significance and medical applications. The study can help scientists understand ancient human population migrations as well as how different human groups are biologically related to one another. From a medical perspective the study of human genetic variation may be important because some disease causing alleles occur at a greater frequency in people from specific geographic regions.

[edit] Genetic variation

Genetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection.

[edit] Measures of variation

"Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes."^[3]

[edit] Single nucleotide polymorphisms

Nucleotide diversity is based on single mutations called single nucleotide polymorphisms (SNPs). The nucleotide diversity between humans is about 0.1%, which is 1 difference per 1,000 base pairs.^[4][5][6] A difference of 1 in 1,000 nucleotides between two humans chosen at random amounts to approximately 3 million nucleotide differences since the human genome has about 3 billion nucleotides. Most of these SNPs are neutral but some are functional and influence phenotypic differences between humans through alleles. It is estimated that a total of 10 million SNPs exist in the human population of which at least 1% are functional (see International HapMap Project).

[edit] Copy number variation

More recently a better understanding of the structure of the genome has been gained with the publication of two examples of full sequences of an individual's genome. This represents a new development because the Human Genome Project and a parallel project by Celera Genomics produced two haploid sequences, both of which were an amalgamation of sequences from many individuals.^[7] Recently the diploid sequences of both Craig Venter and James Watson have been published. Analysis of diploid sequences has shown that non-SNP variation accounts for much more human genetic variation than single nucleotide diversity. This non-SNP variation includes copy number variation and results from deletions, inversions, insertions and duplications. It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to copy number. When copy number variation is included, human to human genetic variation is estimated to be at least 0.5% (99.5% similarity).^{[8][9][10][11][12]} Copy number variations are inherited but can also arise during development.^{[13][14][15][16][17]}

[edit] Epigenetics

Epigenetics is another type of genetic variation. "This type of variation arises from chemical tags that attach to DNA and affect how it gets read. The chemical tags, called epigenetic markings, act as switches that control how genes can be read."^[18] At some alleles, the epigenetic state of the DNA, and associated phenotype, can be inherited transgenerationally.^[19]

[edit] Genetic variability

Genetic variability is a measure of the tendency of individual genotypes in a population to vary (become different) from one another. Variability is different from genetic diversity, which is the amount of variation seen in a particular population.^[20] The variability of a trait describes how much that trait tends to vary in response to environmental and genetic influences.

[edit] Clines

In biology, a cline is a term used to describe a continuum of species, populations, races, varieties, or forms of organisms that exhibit gradual phenotypic and/or genetic differences over a geographical area, typically as a result of environmental heterogeneity.^[21][22][23] In the scientific study of human genetic variation, a gene cline can be rigorously defined and subjected to quantitative metrics.

[edit] Haplogroups

In the study of molecular evolution, a haplogroup is a group of similar haplotypes that share a common ancestor with a single nucleotide polymorphism (SNP) mutation. Haplogroups pertain to deep ancestral origins dating back thousands of years.^[24]

In human genetics, the haplogroups most commonly studied are Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups, both of which can be used to define genetic populations. Y-DNA is passed solely along the patrilineal line, from father to son, while mtDNA is passed down the matrilineal line, from mother to daughter. The Y-DNA and mtDNA may change by chance mutation at each generation.

[edit] Variable number tandem repeats

A variable number tandem repeat (VNTR) is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show variations in length between individuals. Each variant acts as an inherited allele, allowing them to be used for personal or parental identification. Their analysis is useful in genetics and biology research, forensics, and DNA fingerprinting.

There are two principal families of VNTRs: microsatellites and minisatellites. The former are repeats of sequences less than about 5 base pairs in length, while the latter involve longer blocks.

[edit] History and geographic distribution

A 10-year study published in April 2009 analyzed the patterns of variation at 1,327 DNA markers of 121 African populations, 4 African American populations, and 60 non-African populations.^[25][26] The research showed that there is more human genetic diversity in Africa than anywhere else on Earth. The genetic structure of Africans was traced to 14 ancestral population clusters and the ancestral origin of humans was determined to probably be located in southern Africa, near the border of Namibia and South Africa.

Human genetic diversity decreases in native populations with migratory distance from Africa and this is thought to be the result of bottlenecks during human migration, which are events that temporarily reduce population size.^[27][28] It has been shown that variations in skull measurements decrease with distance from Africa at the same rate as the decrease in genetic diversity. This data supports the out of Africa theory over the multiregional origin of modern humans theory. The aforementioned April 2009 study identifies the likely origin of modern human migration as being in southwestern Africa, near the coastal border of Namibia and Angola, and the exit point out of Africa as being in East Africa.^[29]

The recent African origin of modern humans is the mainstream model describing the origin and early dispersal of anatomically modern humans, Homo sapiens sapiens. The theory is known popularly as the (Recent) Out-of-Africa model. The hypothesis originated in the 19th century, with Darwin's Descent of Man, but remained speculative until the 1980s when it was corroborated based on a study of present-day mitochondrial DNA, combined with evidence based on physical anthropology of archaic specimens.

According to both genetic and fossil evidence, archaic Homo sapiens evolved to anatomically modern humans solely in Africa, between 200,000 and 100,000 years ago, with members of one branch leaving Africa by 60,000 years ago and over time replacing earlier human populations such as Neanderthals and Homo erectus. According to this theory around the above time frame one of the African subpopulations went through a process of speciation prohibiting gene flow between African and Eurasian Human populations.

[edit] Population genetics

In the field of population genetics, it is believed that the distribution of neutral polymorphisms among contemporary humans reflects human demographic history. It is believed that humans passed through a population bottleneck before a rapid expansion coinciding with migrations out of Africa leading to an African-Eurasian divergence around 100,000 years ago (ca. 5,000 generations), followed by a European-Asian divergence about 40,000 years ago (ca. 2,000 generations). Richard G. Klein, Nicholas Wade and Spencer Wells, among others, have postulated that modern humans did not leave Africa and successfully colonize the rest of the world until as recently as 60,000 - 50,000 years B.P., pushing back the dates for subsequent population splits as well.

The rapid expansion of a previously small population has two important effects on the distribution of genetic variation. First, the so-called founder effect occurs when founder populations bring only a subset of the genetic variation from their ancestral population. Second, as founders become more geographically separated, the probability that two individuals from different founder populations will mate becomes smaller. The effect of this assortative mating is to reduce gene flow between geographical groups, and to increase the genetic distance between groups. The expansion of humans from Africa affected the distribution of genetic variation in two other ways. First, smaller (founder) populations experience greater genetic drift because of increased fluctuations in neutral polymorphisms. Second, new polymorphisms that arose in one group were less likely to be transmitted to other groups as gene flow was restricted.

Our history as a species also has left genetic signals in regional populations. For example, in addition to having higher levels of genetic diversity, populations in Africa tend to have lower amounts of linkage disequilibrium than do populations outside Africa, partly because of the larger size of human populations in Africa over the course of human history and partly because the number of modern humans who left Africa to colonize the rest of the world appears to have been relatively low (Gabriel et al. 2002). In contrast, populations that have undergone dramatic size reductions or rapid expansions in the past and populations formed by the mixture of previously separate ancestral groups can have unusually high levels of linkage disequilibrium (Nordborg and Tavare 2002).

Many other geographic, climatic, and historical factors have contributed to the patterns of human genetic variation seen in the world today. For example, population processes associated with colonization, periods of geographic isolation, socially reinforced endogamy, and natural selection all have affected allele frequencies in certain populations (Jorde et al. 2000b; Bamshad and Wooding 2003). In general, however, the recency of our common ancestry and continual gene flow among human groups have limited genetic differentiation in our species.

[edit] Distribution of variation

The distribution of genetic variants within and among human populations are impossible to describe succinctly because of the difficulty of defining a "population," the clinal nature of variation, and heterogeneity across the genome (Long and Kittles 2003). In general, however, an average of 85% of genetic variation exists within local populations, ~7% is between local populations within the same continent, and ~8% of variation occurs between large groups living on different continents,. (Lewontin 1972; Jorde et al. 2000a; Hinds et al. 2005). The recent African origin theory for humans would predict that in Africa there exists a great deal more diversity than elsewhere, and that diversity should decrease the further from Africa a population is sampled. Long and Kittles show that indeed, African populations contain about 100% of human genetic diversity, whereas in populations outside of Africa diversity is much reduced, for example in their population from New Guinea only about 70% of human variation is captured.

[edit] Phenotypic variation

Sub-Saharan Africa has the most human genetic diversity and the same has been shown to hold true for phenotypic diversity.^[30] Genetic diversity decreases smoothly with migratory distance from that region, which many scientists believe to be the origin of modern humans, and that decrease is mirrored by a decrease in phenotypic variation. Skull measurements are an example of a physical attribute whose within-population variation decreases with distance from Africa.

The distribution of many physical traits resembles the distribution of genetic variation within and between human populations (American Association of Physical Anthropologists 1996; Keita and Kittles 1997). For example, ~90% of the variation in human head shapes occurs within continental groups, and ~10% separates groups, with a greater variability of head shape among individuals with recent African ancestors (Relethford 2002). Skull measurements, however, can be used to help determine the geographic ancestry of a deceased individual.

[edit] Skin color

A prominent exception to the common distribution of physical characteristics within and among groups is skin color. Approximately 10% of the variance in skin color occurs within groups, and ~90% occurs between groups (Relethford 2002). This distribution of skin color and its geographic patterning — with people whose ancestors lived predominantly near the equator having darker skin than those with ancestors who lived predominantly in higher latitudes — indicate that this attribute has been under strong selective pressure. Darker skin appears to be strongly selected for in equatorial regions to prevent sunburn, skin cancer, the photolysis of folate, and damage to sweat glands (Sturm et al. 2001; Rees 2003).

A leading hypothesis for the selection of lighter skin in higher latitudes is that it enables the body to form greater amounts of vitamin D, which helps prevent rickets (Jablonski 2004). Evidence for this includes the finding that a substantial portion of the differences of skin color between Europeans and Africans resides in a single gene, SLC24A5 the threonine-111 allele of which was found in 98.7 to 100% among several European samples, while the alanine-111 form was found in 93 to 100% of samples of Africans, East Asians and Indigenous Americans (Lamason et al. 2005). However, the vitamin D hypothesis is not universally accepted (Aoki 2002), and lighter skin in high latitudes may correspond simply to an absence of selection for dark skin (Harding et al. 2000). Melanin which serves as the pigment, is located in the epidermis of the skin, and is based on hereditary gene expression.

Because skin color has been under strong selective pressure, similar skin colors can result from convergent adaptation rather than from genetic relatedness. Sub-Saharan Africans, populations from southern India, and Indigenous Australians have similar skin pigmentation, but genetically they are no more similar than are other widely separated groups. Furthermore, in some parts of the world in which people from different regions have mixed extensively, the connection between skin color and ancestry has been substantially weakened (Parra et al. 2004). In Brazil, for example, skin color is not closely associated with the percentage of recent African ancestors a person has, as estimated from an analysis of genetic variants differing in frequency among continent groups (Parra et al. 2003).

Considerable speculation has surrounded the possible adaptive value of other physical features characteristic of groups, such as the constellation of facial features observed in many eastern and northeastern Asians (Guthrie 1996). However, any given physical characteristic generally is found in multiple groups (Lahr 1996), and demonstrating that environmental selective pressures shaped specific physical features will be difficult, since such features may have resulted from sexual selection for individuals with certain appearances or from genetic drift (Roseman 2004).

[edit] Skeletal characteristics

Forensic anthropologists can determine race (e.g. Asian, African, or European ancestry) from skeletal remains with a high degree of accuracy by conducting bone analysis.^[31] Studies have shown that individual test methods such as midfacial measurements and femur traits can be over 80 percent accurate, and in combination can achieve high levels of accuracy. The skeletons of mixed-race individuals can, however, exhibit characteristics of more than one racial group.

[edit] Categorization of the world population

New data on human genetic variation has reignited the debate surrounding race. Most of the controversy surrounds the question of how to interpret this new data, and whether conclusions based on existing data are sound. A large majority of researchers endorse the view that continental groups do not constitute different subspecies. However, other researchers still debate whether evolutionary lineages should rightly be called "races". These questions are particularly pressing for biomedicine, where self-described race is often used as an indicator of ancestry.

Although the genetic differences among human groups are relatively small, these differences in certain genes such as duffy, ABCC11, SLC24A5, called ancestry-informative markers (AIMs) nevertheless can be used to reliably situate many individuals within broad, geographically based groupings or self-identified race. For example, computer analyses of hundreds of polymorphic loci sampled in globally distributed populations have revealed the existence of genetic clustering that roughly is associated with groups that historically have occupied large continental and subcontinental regions (Rosenberg et al. 2002; Bamshad et al. 2003).

Some commentators have argued that these patterns of variation provide a biological justification for the use of traditional racial categories. They argue that the continental clusterings correspond roughly with the division of human beings into sub-Saharan Africans; Europeans, Western Asians, Central Asians, Southern Asians and Northern Africans; Eastern Asians, Southeast Asians, Polynesians and Native Americans; and other inhabitants of Oceania (Melanesians, Micronesians & Australian Aborigines) (Risch et al. 2002). Other observers disagree, saying that the same data undercut traditional notions of racial groups (King and Motulsky 2002; Calafell 2003; Tishkoff and Kidd 2004). They point out, for example, that major populations considered races or subgroups within races do not necessarily form their own clusters.

Furthermore, because human genetic variation is clinal, many individuals affiliate with two or more continental groups. Thus, the genetically based "biogeographical ancestry" assigned to any given person generally will be broadly distributed and will be accompanied by sizable uncertainties (Pfaff et al. 2004).

In many parts of the world, groups have mixed in such a way that many individuals have relatively recent ancestors from widely separated regions. Although genetic analyses of large numbers of loci can produce estimates of the percentage of a person's ancestors coming from various continental populations (Shriver et al. 2003; Bamshad et al. 2004), these estimates may assume a false distinctiveness of the parental populations, since human groups have exchanged mates from local to continental scales throughout history (Cavalli-Sforza et al. 1994; Hoerder 2002). Even with large numbers of markers, information for estimating admixture proportions of individuals or groups is limited, and estimates typically will have wide confidence intervals or CIs (Pfaff et al. 2004).

[edit] Lewontin's Fallacy

In 2003 A. W. F. Edwards wrote a paper called Lewontin's Fallacy, rebuking the argument that because most genetic variation is within-group, classification of humans is not possible. He claimed that this conclusion ignores the fact that most of the information that distinguishes populations is hidden in the correlation structure of the data and not simply in the variation of the individual factors. Edwards concludes that "It is not true that 'racial classification is ... of virtually no genetic or taxonomic significance' or that 'you can't predict someone’s race by their genes'."^[32] Undeterred, in an article titled "Confusions About Human Races"^[33] published in 2006, Lewontin maintains that race is no more than a social construct.

[edit] Genetic clustering

Genetic data can be used to infer population structure and assign individuals to groups that often correspond with their self-identified geographical ancestry. Recently, Lynn Jorde and Steven Wooding argued that "Analysis of many loci now yields reasonably accurate estimates of genetic similarity among individuals, rather than populations. Clustering of individuals is correlated with geographic origin or ancestry."^[34]

[edit] Admixture

Triangle plot shows average admixture of five North American ethnic groups. Individuals that self-identify with each group can be found at many locations on the map, but on average groups tend to cluster differently.

Miscegenation between two populations reduces the genetic distance between the populations. During the Age of Discovery which began in the early 15th century, European explorers sailed all across the globe reaching all the major continents. In the process they came into contact with many populations that had been isolated for thousands of years. It is generally accepted that the Tasmanian aboriginals were the most isolated group on the planet. They were driven to extinction by European explorers, however a number of their descendants survive today as a result of admixture with Europeans. This is an example of how modern migrations have begun to reduce the genetic divergence of the human race.

The demographic composition of the old world has not changed significantly since the age of discovery. However, the new world demographics were radically changed within a short time following the voyage of Columbus. The colonization of Americas brought Native Americans into contact with the distant populations of Europe, Africa, and Asia. As a result many countries in the Americas have significant and complex multiracial populations. Furthermore many who identify themselves by only one race still have multiracial ancestry.

[edit] Health

Differences in allele frequencies contribute to group differences in the incidence of some monogenic diseases, and they may contribute to differences in the incidence of some common diseases (Risch et al. 2002; Burchard et al. 2003; Tate and Goldstein 2004). For the monogenic diseases, the frequency of causative alleles usually correlates best with ancestry, whether familial (for example, Ellis-van Creveld syndrome among the Pennsylvania Amish), ethnic (Tay-Sachs disease among Ashkenazi Jewish populations), or geographical (hemoglobinopathies among people with ancestors who lived in malarial regions). To the extent that ancestry corresponds with racial or ethnic groups or subgroups, the incidence of monogenic diseases can differ between groups categorized by race or ethnicity, and health-care professionals typically take these patterns into account in making diagnoses.^{[citation needed]}

Even with common diseases involving numerous genetic variants and environmental factors, investigators point to evidence suggesting the involvement of differentially distributed alleles with small to moderate effects. Frequently cited examples include hypertension (Douglas et al. 1996), diabetes (Gower et al. 2003), obesity (Fernandez et al. 2003), and prostate cancer (Platz et al. 2000). However, in none of these cases has allelic variation in a susceptibility gene been shown to account for a significant fraction of the difference in disease prevalence among groups, and the role of genetic factors in generating these differences remains uncertain (Mountain and Risch 2004).

Neil Risch of Stanford University has proposed that self-identified race/ethnic group could be a valid means of categorization in the USA for public health and policy considerations.^[35][36] While a 2002 paper by Noah Rosenberg's group makes a similar claim "The structure of human populations is relevant in various epidemiological contexts. As a result of variation in frequencies of both genetic and nongenetic risk factors, rates of disease and of such phenotypes as adverse drug response vary across populations. Further, information about a patient’s population of origin might provide health care practitioners with information about risk when direct causes of disease are unknown."^[37]

[edit] Genome projects

Human genome projects are scientific endeavors that determine or study the structure of the human genome. The Human Genome Project was a landmark genome project.

[edit] See also

• Race and genetics
• Archaeogenetics
• Human evolutionary genetics
• Multiregional hypothesis
• Recent single origin hypothesis
• Genetic history of Europe
• Genetic history of South Asia
• African admixture in Europe
• Isolation by distance
• Genealogical DNA test
• Y-DNA haplogroups by ethnic groups
• Human genetic clustering

Projects:

• 1000 Genomes Project
• Human Variome Project
• International HapMap Project

[edit] References

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[edit] External links

• Human Genome Variation Society
• Pennisi, Elizabeth (2007-12-21). "BREAKTHROUGH OF THE YEAR: Human Genetic Variation". Science (AAAS) 318 (5858): 1842–3. doi:10.1126/science.318.5858.1842. http://www.sciencemag.org/cgi/content/full/318/5858/1842.