What Genomics Says about Being Human

by carolinastaff
Full body x-ray

The revolution in DNA sequencing has led to an explosion in genomics, adding remarkable depth to understanding of what it means to be human.

Nucleotide sequences

In the last decade, the cost of determining 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–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. Earlier in 2020, the New York Genome Center (NYGC), obtained high-coverage with a total of 3,202 samples sequenced. 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, 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.

The Genome Age: Exploring Human Variation and Evolution

Whole genome comparisons

Whole genome comparisons confirm that humans are remarkably like 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 million 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 have been disabled over time 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 and human culture

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 many 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. DNALC Making Lactose-Free Milk Kit allows students to make these comparisons in a lab setting.

Now that we know how our genome has changed in the 6 million years since we diverged from a common ancestor with chimpanzees and how students can include their own mitochondrial DNA sequence in a study to show that all humans alive today share a common ancestor who lived about 150,000 years ago in Africa, it is time to explore what the analysis of ancient DNA says about us and our nearest relative. This has been made possible by the perfection of methods to amplify and assemble nucleotide sequences from the small amount of DNA that is preserved in bones dating back as far as 60,000 years.

The Science Behind Lactose Intolerance

Neanderthal DNA analysis

Since their discovery in Germany’s Neander Valley in 1856, the heavyset bones of Neanderthal have fascinated scientists, as well as the general public. Neanderthal ranged throughout Europe, the Middle East, and western Russia beginning about 300,000 years ago and became extinct about 30,000 years ago. With mostly the same anatomical features as Homo sapiens, including a larger average brain volume, Neanderthal was our closest hominid relative. However, illustrations and museum reconstructions traditionally cast Neanderthal as a lumbering brute. A primitive tool set and scant evidence of ceremonial burials completed the impression of Neanderthal as different from Homo sapiens (thinking man).

The fact that Neanderthal shared the same geographical range with modern humans for at least 10,000 years raises several questions. What is our genetic relationship to Neanderthal? Was Neanderthal the ancestor of modern Europeans? Did he interbreed with our ancestors? Recent analysis of the Neanderthal genome has provided definitive answers to these questions and recast Neanderthal in a different light.

A 1997 analysis of a sequence from the Neanderthal mitochondrial genome conclusively showed that modern humans are not directly descended from Neanderthal but that we shared a common ancestor about 600,000 years ago. However, because the mitochondrial genome is inherited only through a female lineage, this analysis was mute on whether our ancestors interbred with Neanderthal. The answer to that question had to await the publication, in May 2010, of the draft sequence of the Neanderthal nuclear genome.

The Neanderthal and chimpanzee genomes and genomes of contemporary humans were compared to identify “fixed” nucleotide substitutions–locations where all humans share the same nucleotide but where Neanderthal and chimp share a different (ancestral) nucleotide. This genome-wide analysis turned up only 78 nucleotide substitutions that cause amino acid differences in proteins between humans and Neanderthal. Pair-wise comparison of single nucleotide polymorphisms (SNPs) between Neanderthal and contemporary humans showed a significantly greater number of matches with Europeans and Asians than with Africans.

Neanderthal matched long-range SNP patterns (haplotypes) in 10 of 12 Asian and European chromosome regions showing high SNP diversity. This provided strong evidence that Neanderthal contributed 1% to 4% of the DNA of modern Europeans and Asians. The “gene flow” from Neanderthal into the human genome likely occurred 50,000 to 80,000 years ago in the Middle East, after modern humans migrated out of Africa but prior to their dispersion into Europe and Asia.

Detailed analysis of individual genes paints a picture of a decidedly “modern” Neanderthal. Some Neanderthal individuals have a point mutation in the gene for the melanocorticoid ligand receptor (mclr) that regulates skin and hair pigmentation. This mutation is biologically equivalent to mclr mutations that produce the characteristic “Irish” phenotype of fair skin and red hair. Fair-skinned Neanderthals would have absorbed more UVB light needed to synthesize vitamin D, an advantage during winter months at higher latitudes.

Neanderthal also shares with contemporary humans a key mutation of the TAS2R38 receptor on the tongue that diminishes perception of bitter taste. This may have freed hominids to include more bitter-tasting plants in their diet, as opposed to avoiding them. Neanderthal also shares with every human 2 amino acid changes in the FOXP2 protein, which appear crucial to articulate speech. Still, it is impossible to tell if Neanderthal had language or even when this ability developed in humans.

Modern human DNA

During most of the vast span of evolution, including intermixing with Neanderthal, Homo sapiens subsisted entirely by hunting and gathering. The domestication of plants was perhaps the single greatest civilizing factor in human history. The increased productivity of cereal crops made it possible for fewer and fewer farmers to produce enough food for growing numbers of non-farmers–artisans, engineers, teachers, administrators, and merchants–freeing them to develop other elements of culture.

Luca Cavalli-Sforza first described this “Neolithic transition” from hunter-gatherers to farmers in genetic terms, when he identified an east-west gradient in the allele frequencies of blood proteins. This appeared to mirror the spread of agriculture across Europe, beginning about 10,000 years ago and progressing at a rate of about 1 km per year from the site of wheat and barley domestication in southeastern Turkey.

A cemetery that served an ancient farming community was discovered in Derenburg, central Germany. Recent DNA analysis of human remains found in the cemetery provides strong support for Cavalli-Sforza’s demic diffusion model, in which waves of Neolithic farmers mixed their genes with indigenous hunter-gatherers as they spread across Europe in search of new fields. (Demic refers to a deme, a local population of a species.)

Mitochondrial SNPs from 22 skeletons in the cemetery dated to 7,100 years ago were compared with SNPs from contemporary European populations. The strongest associations were with modern populations from central Europe, as well as from Turkey, Syria, and Iraq. This is the genetic signature one would expect of agriculturalists arriving from the Middle East and mixing with, but not completely replacing, local hunter-gatherer populations. Your students can look at their own ability to taste a bitter flavor Using a Single Nucleotide Polymorphism (SNP) to Predict Bitter Tasting Ability Kit, which explores the molecular basis of the inherited ability to taste the bitter chemical phenylthiocarbamide (PTC). After determining their ability to taste PTC using taste paper, they use safe saline mouthwash and Chelex® extraction to obtain a sample of their own DNA and amplify a 221-nucleotide region of the PTC taste receptor gene. This is a great way for students to get to know themselves on a molecular level.

It is obvious that the evolution of Homo sapiens’ superior brain provided a competitive advantage over other creatures. However, the cemetery at Derenburg provides evidence that the human-directed evolution of plants–agriculture–provided an adaptive advantage that allowed farmers, and their genes, to gain ascendancy over their hunter-gatherer forebears.


David A. Micklos
Founder and Executive Director
DNA Learning Center at Cold Spring Harbor Laboratory
Cold Spring Harbor, NY

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