Figure 4–79 Tracing the course of human history by analyses of genome sequences. The map shows the routes of the earliest successful human migrations. Dotted lines indicate two alternative routes that our ancestors are thought to have taken out of Africa. DNA sequence comparisons suggest that modern Europeans descended from a small ancestral population that existed about 30,000 to 50,000 years ago. In agreement, archaeological findings suggest that the ancestors of modern native Australians (solid red arrows)—and of modern European and middle Eastern populations—reached their destinations about 45,000 years ago. Even more recent studies, comparing the genome sequences of living humans with those of Neanderthals and another extinct population from southern Siberia (the Denisovans), suggest that our exit from Africa was a bit more convoluted, while also revealing that a number of our ancestors interbred with these hominid neighbors as they made their way across the globe. (modified from
P. Forster and S. matsumura, Science 308:965–966, 2005.) density of known genes a polymorphism, the variants must be common enough to give a reasonably high probability that the genomes of two randomly chosen individuals will differ at the given site; a probability of 1% is commonly chosen as the cutoff. Two human genomes sampled from the modern world population at random will differ at approximately 2.5 × 106 such sites (1 per 1300 nucleotide pairs). As will be described in the overview of genetics in Chapter 8, SNPs in the human genome can be extremely useful for genetic mapping analyses, in which one attempts to associate specific traits (phenotypes) with specific DNA sequences for medical or scientific purposes (see p. 493). But while useful as genetic markers, there is good evidence that most of these SNPs have little or no effect on human fitness. This is as expected, since deleterious variants will have been selected against during human evolution and, unlike SNPs, should therefore be rare.
Against the background of ordinary SNPs inherited from our prehistoric ancestors, certain sequences with exceptionally high mutation rates stand out. A dramatic example is provided by CA repeats, which are ubiquitous in the human genome and in the genomes of other eukaryotes. Sequences with the motif (CA)n are replicated with relatively low fidelity because of a slippage that occurs between the template and the newly synthesized strands during DNA replication; hence, the precise value of n can vary over a considerable range from one genome to the next. These repeats make ideal DNA-based genetic markers, since most humans are heterozygous, having inherited one repeat length (n) from their mother and a different repeat length from their father. While the value of n changes sufficiently rarely that most parent–child transmissions propagate CA repeats faithfully, the changes are sufficiently frequent to maintain high levels of heterozygosity in the human population. These and some other simple repeats that display exceptionally high variability therefore provide the basis for identifying individuals by DNA analysis in crime investigations, paternity suits, and other forensic applications (see Figure 8–39).
While most of the SNPs and CNVs in the human genome sequence are thought to have little or no effect on phenotype, a subset of the genome sequence variations must be responsible for the heritable aspects of human individuality. We know that even a single nucleotide change that alters one amino acid in a protein can cause a serious disease, as for example in sickle-cell anemia, which is caused by such a mutation in hemoglobin (Movie 4.3). We also know that gene dosage—a doubling or halving of the copy number of some genes—can have a profound effect on development by altering the level of gene product, as can changes in regulatory DNA sequences. There is therefore every reason to suppose that some of the many differences between any two human beings will have substantial
Figure 4–80 Detection of copy number variations on human chromosome 17.