Humanness as a numbers game

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: Human beings may not think of themselves as the centre of all creation any longer, but they are regarded as unique, at least among their close primate cousins. The “why” may just have begun to fall in place, unveiling a jigsaw puzzle that has interested researchers for long but with few tangible clues to advance a plausible explanation.

From time to time, the role played by chromosomal variations in the genome has helped explain certain phenomena, such as Down’s syndrome, a genetic disorder caused by the additional presence of the entire or part of the 21st chromosome that is manifested by major and minor variations in body structure resulting in impairment of cognitive ability and physical growth as well as facial appearance.

On the other extreme of chromosomal abnormality, non-disjunction of a chromosome results when homologous chromosome pairs do not separate during meiosis. These variants, resulting in deletion, duplication, translocation or inversion, are all examples of chromosomal abnormalities. The Turner syndrome (females missing one X chromosome) is another example that manifests itself in several ways, including amenorrhoea, sterility, obesity and so on. Thus, the copy number of genes has long been associated with certain physical and physiological irregularities leading to impairments.

Recent advances in molecular studies and comparative genomic hybridisation, that came into the limelight for their fascinating applications in oncology, have begun to shed light on yet another facet of human behaviour that has eluded characterisation until now.

James Sikela of the University of Colorado, Denver and Health Sciences Center in Aurora, and his colleagues have come out with a novel hypothesis on the role of gene copy number variation in humans and our closest relatives. In a recent paper published in Genome Research, comparisons between DNA from more than 24,000 known human genes, with DNA from baboons, bonobos, chimpanzees, gibbons, gorillas, lemurs, macaques, marmosets and orangutans elicited a bewildering pattern. Quite an exhaustive and comprehensive project of research, no one till date quite seems to have probed such vast data among such a diverse group of closely related species.

The crux of their findings? More than 4,000 genes showed lineage-specific changes in their copy number, with the numbers steadily increasing species-to-species over evolutionary time. Interestingly, humans had only 84 genes with increased copy numbers over those of our closest relatives. In contrast, lemurs, which have evolved over 60 million years, have 1,180 genes with extra copies. “This is further evidence that genomic differences between humans and other primates is far, far more complex than we originally imagined they might be,” observed Ajit Varki, who studies human/chimpanzee differences at the University of California, San Diego. “However,” he cautions, “many of the differences may or may not be relevant for explaining ‘humanness’.”

There is a silver lining to this observation. Jonathan Sebat, a geneticist at Cold Spring Harbor Laboratory in New York State, who specialises in copy number variation, is ecstatic in calling the results “quite tantalising”, but also feels that the report may have stretched things a little in its speculation on the biological effects. Unfazed, Sikela opines the paper is meant to be “hypothesis generating” and expects several genes to be investigated.

One such gene is aquaporin7, of which humans have five copies, whereas the other primates have just two, prompting researchers to suggest that the gene may be involved in exercise-induced sweating and endurance running, a feature unique among humans. Likewise, gorillas have many extra genes known to play a role in the excretion of toxins. This makes sense, too, for gorillas eat many toxin-rich plants.

These findings point to regions of chromosomes in various species that seem particularly predisposed to gene duplication or loss, and argue that these “gene nurseries” may well be hot spots for evolution. “It’s a double-edged sword,” avers Sikela. “It could easily lead to a disease, but the upside is it increases variation that evolution can use. It’s more evolutionary fuel.” Not surprisingly, the family of genes that may broaden the gorilla’s diet are restricted in humans and linked to a disease called DiGeorge syndrome.

Sunil Ahuja, who discovered in his lab at the University of Texas Health Science Center at San Antonio a copy number variation that strongly protects people from HIV, is cautiously optimistic when he says proving the link between extra or missing genes and function would warrant more work.

Heady days are here for science to peg away at genetic mysteries and the mystiques of human form and function, physiology and emotions, and that last untrammelled bastion of human behaviour—humanness!