Figure 8–49 Using genetics to determine the order of function of genes. In normal cells, secretory proteins are loaded into vesicles, which fuse with the plasma membrane to secrete their contents into the extracellular medium. Two mutants, A and B, fail to secrete proteins. In mutant A, secretory proteins accumulate in the ER. In mutant B, secretory proteins accumulate in the Golgi. In the double mutant AB, proteins accumulate in the ER; this indicates that the gene defective in mutant A acts before the gene defective in mutant B in the secretory pathway.
population is so large, spontaneous, nonlethal mutations have arisen in all human genes—many times over. A substantial proportion of these remain in the genomes of present-day humans. The most deleterious of these mutations are discovered when the mutant individuals call attention to themselves by seeking medical help.
With the recent advances that have enabled the sequencing of entire human genomes cheaply and quickly, we can now identify such mutations and study their evolution and inheritance in ways that were impossible even a few years ago. By comparing the sequences of thousands of human genomes from all around the world, we can begin to identify directly the DNA differences that distinguish one individual from another. These differences hold clues to our evolutionary origins and can be used to explore the roots of disease.
Linked Blocks of Polymorphisms Have Been Passed Down from Our Ancestors
When we compare the sequences of multiple human genomes, we find that any two individuals will differ in roughly 1 nucleotide pair in 1000. Most of these variations are common and relatively harmless. When two sequence variants coexist in the population and both are common, the variants are called polymorphisms. The majority of polymorphisms are due to the substitution of a single nucleotide, called single-nucleotide polymorphisms or SNPs (Figure 8–50). The rest are due largely to insertions or deletions—called indels when the change is small, or copy number variations (CNVs) when it is large. Although these common variants can be found throughout the genome, they are not scattered randomly—or even independently. Instead, they tend to travel in groups called haplotype blocks—combinations of polymorphisms that are inherited as a unit.
To understand why such haplotype blocks exist, we need to consider our evolutionary history. It is thought that modern humans expanded from a relatively small population—perhaps around 10,000 individuals—that existed in Africa about 60,000 years ago. Among that small group of our ancestors, some individuals will have carried one set of genetic variants, others a different set. The chromosomes of a present-day human represent a shuffled combination of chromosome segments from different members of this small ancestral group of people. Because only about two thousand generations separate us from them, large segments of these ancestral chromosomes have passed from parent to child, unbroken by the crossover events that occur during meiosis. As described in Chapter 5, only a few crossovers occur between each set of homologous chromosomes during each meiosis (see Figure 5–53).
As a result, certain sets of DNA sequences—and their associated polymorphisms—have been inherited in linked groups, with little genetic rearrangement across the generations. These are the haplotype blocks. Like genes that exist in different allelic forms, haplotype blocks also come in a limited number of variants that are common in the human population, each representing a combination of DNA polymorphisms passed down from a particular ancestor long ago.
Figure 8–50 Single-nucleotide polymorphisms (SNPs) are sites in the genome where two or more alternative choices of a nucleotide are common in the population. Most such variations in the human genome occur at locations where they do not significantly affect a gene’s function.
Polymorphisms Can Aid the Search for Mutations Associated with Disease