When a new neutral mutation occurs in a population of constant size N that is undergoing random mating, the probability that it will ultimately become fixed is approximately 1/(2N). This is because there are 2N copies of the gene in the diploid population, and each of them has an equal chance of becoming the predominant version in the long run. For those mutations that do become fixed, the mathematics shows that the average time to fixation is approximately 4N generations. Detailed analyses of data on human genetic variation have suggested an ancestral population size of approximately 10,000 at the time when the current pattern of genetic variation was largely established. With a population that has reached this size, the probability that a new, selectively neutral mutation would become fixed is small (1/20,000), while the average time to fixation would be on the order of 800,000 years (assuming a 20-year generation time). Thus, while we know that the human population has grown enormously since the development of agriculture approximately 15,000 years ago, most of the present-day set of common human genetic variants reflects the mixture of variants that was already present long before this time, when the human population was still small.
Similar arguments explain another phenomenon with important practical implications for genetic counseling. In an isolated community descended from a small group of founders, such as the people of Iceland or the Jews of Eastern individual with rare allele
Europe, genetic variants that are rare in the human population as a whole can often be present at a high frequency, even if those variants are mildly deleterious (Figure 4–78).
A great Deal Can be learned from Analyses of the variation Among Humans
Even though the common variant gene alleles among modern humans originate from variants present in a comparatively tiny group of ancestors, the total number of variants now encountered, including those that are individually rare, is very large. New neutral mutations are constantly occurring and accumulating, even though no single one of them has had enough time to become fixed in the vast modern human population.
From detailed comparisons of the DNA sequences of a large number of modern humans located around the globe, scientists can estimate how many generations have elapsed since the origin of a particular neutral mutation. From such data, it has been possible to map the routes of ancient human migrations. For example, by combining this type of genetic analysis with archaeological findings, scientists have been able to deduce the most probable routes that our ancestors took when they left Africa 60,000 to 80,000 years ago (Figure 4–79).
We have been focusing on mutations that affect a single gene, but these are not the only source of variation. Another source, perhaps even more important but missed for many years, lies in the many duplications and deletions of large blocks of human DNA. When one compares any individual human with the standard reference genome in the database, one will generally find roughly 100 differences involving gain or loss of long sequence blocks, totaling perhaps 3 million nucleotide pairs. Some of these copy number variations (CNVs) will be very common, presumably reflecting relatively ancient origins, while others will be present in only a small minority of people (Figure 4–80). On average, nearly half of the CNVs contain known genes. CNVs have been implicated in many human traits, including color blindness, infertility, hypertension, and a wide variety of disease susceptibilities. In retrospect, this type of variation is not surprising, given the prominent role of DNA addition and DNA loss in vertebrate evolution.
The intraspecies variations that have been most extensively characterized, however, are single-nucleotide polymorphisms (SNPs). These are simply points in the genome sequence where one large fraction of the human population has one nucleotide, while another substantial fraction has another. To qualify as
Figure 4–78 How founder effects determine the set of genetic variants in a population of individuals belonging to the same species. This example illustrates how a rare allele (red) can become established in an isolated population, even though the mutation that produced it has no selective advantage—or is mildly deleterious.