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What Genomics Says about Being Human Part I

By David Micklos
DNA Learning Center (DNALC), Cold Spring Harbor Laboratory

DNA sample

Please see Part II of this fascinating look at the genetic relationship between Neanderthal and Homo sapiens. —Ed.

In the last 5 years, the cost of determing the nucleotide sequence of chromosomes has decreased by at least a thousandfold to about $1 per megabase (million base pairs). This was achieved by eliminating the labor-intensive steps of bacterial cloning needed to amplify sufficient quantities of DNA to analyze. So-called “next generation” DNA sequencers replace millions of bacterial colonies grown on thousands of plates with millions of amplified PCR colonies (spots where a single sequence of DNA has been chemically amplified using the polymerase chain reaction) on a single glass slide. Machines currently being tested—essentially DNA microscopes—eliminate any amplification step and develop sequences directly from individual DNA molecules.

This revolution in DNA sequencing has led to an explosion in the field of genomics, which analyzes the entire complement of DNA, genes, and chromosomes that determine the genetic identity of a living organism. Although the first human genome was laboriously sequenced over a 15-year period at a cost of several billion dollars, additional genomes costing only tens of thousands of dollars are now readily “scaffolded” (constructed) against that standard. To date, whole genome sequences have been published for about 20 humans, but the 1,000 Genomes Project now underway will provide a large-scale survey of human genetic variation. Comparison of genome sequences, from different humans and different species, has added remarkable depth to our understanding of what it means to be human.

A comparison of single nucleotide polymorphisms (SNPs), or point mutations, in genomes from the 3 old-world human populations provides strong support for the “out of Africa” model, which posits that all modern humans are descended from a recent African ancestor. On average, any 2 human chromosomes differ by one nucleotide in 1,000. However, consistent with African genomes being older and having accumulated mutations over a longer period of time, African chromosomes have about 15% more SNPs than do European or Asian chromosomes. Also, most Asian and European variations are a subset of variations found in Africans, suggesting that Asian and European populations are derived from an African source.

Whole genome comparisons confirm that humans are remarkably similar to our nearest relative, the chimpanzee. At the sequence level, only about 1% of nucleotides differ between the 2 species. Human and chimp chromosomes conserve large regions of synteny (identical gene order), and about 30% of human and chimp genes encode identical amino acid sequences. This suggests that major phenotypic differences between humans and chimps are due primarily to differences in gene regulation, as well as to alternative mRNA splicing that creates different protein configurations.

Many biologists are interested in finding examples of genes that have evolved since humans and chimps split from a common ancestor about 6 to 7 million years ago. Olfactory receptors (ORs) are the largest and one of the fastest-evolving gene families. Although mammals have a repertoire of about 1,000 OR genes, many of these over time have been disabled by mutations. About 800 ORs are functional in mice, but chimps have only 600—a loss of 200 ORs (or 25%) in the 80 million years since the 2 groups split from a common ancestor.

Humans have lost a similar proportion in the relatively brief span of time since they and chimps split from a common ancestor, and about 60 more are in the process of being lost. The exact reason for this accelerating loss of olfactory receptors is unknown. Presumably, many olfactory functions in identifying food sources, marking territory, and finding mates were replaced by increasing brain power.

The lactase gene on human chromosome 15 shows evidence of strong selection in the last 7,000 years and illustrates that human culture has also influenced genome evolution. The lactase enzyme allows infants to digest milk, but lactase production decreases after weaning, and adult primates cannot digest whole milk. Although the vast majority of adults from cultures that did not traditionally raise cattle are lactose intolerant, 50 to 90% of adults in dairying populations in Europe and Africa can readily digest milk.

Dairying provided selective pressure for DNA variations that changed gene regulation to allow lactase activity to persist into adulthood. Thus, many European and African populations show evidence of a “selective sweep” that eliminated genetic diversity in a 300,000-base pair region surrounding the lactase gene in favor of several specific SNPs. Located 14,000 nucleotides upstream of the lactase gene, these mutations act as enhancers to maintain lactase expression in adulthood. The presence of 4 different mutations that confer lactose tolerance shows independent (convergent) evolution of this trait in different human populations.

In the next articles in this series, I will explore what we have learned from looking further back to the genomes of lower animals—and forward to the recent genomes of Ötzi the Iceman, Neanderthal, and other hominid ancestors. Look for these articles in future issues of Carolina Tips®.