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How we ape the ape for our genome!

THE GENOME is the entire collection of the genetic material of an organism. Genes are strung together in it, just as sentences are in the chapters of a book. Each chapter is a chromosome. Chemical analysis of this genetic material reveals it to be made of long chain polymeric molecules of DNA. These are usually put together in the form of two interlocking strands, quite like a zipper is. When heated, the two strands come apart. When cooled slowly back, they zip together in perfect register - no blips or mismatch. In the true tradition of science, which honours pioneer discoverers, one strand of this duplex is informally referred to as the Watson strand and the other, Crick. As with the zipper, each strand- indeed each tooth in it- recognises and pairs up in perfect match with its counterpart in the other strand.

Here is an experiment to check Charles Darwin's proposal that we humans descended from the apes. In today's terms this means that the human genome has its provenance in the ape genome. Or that human DNA is remarkably close to the DNA of the apes.

Take some human DNA and some ape DNA. Dissolve them together in a beaker-ful of water and heat the solution to boiling. You will end up with four strands of DNA- human "Watson", human "Crick", ape Watson and ape Crick. Cool the solution back to room temperature. What do you expect? The human DNA should reassemble and so should the monkey DNA. What if Darwin is right, that we came from the apes? If so, human and ape DNA sequences should be remarkably close and thus match pretty much. In that case, the human DNA Watson strand can just as well pair up with an ape Crick strand- just as it does with the human Crick. There should be very few blips or mismatches in the two mixed or hybrid zippers.

When Dr. Mary Claire King (then at Berkeley) and Drs C. G. Sibley and J. E. Ahlquist of San Francisco State University did such experiments over 20 years ago, they ended up with exactly this result. The genetic material of us humans is remarkably close to that of the chimpanzee. The closeness is a revealing 98.4 per cent. Darwin is right- we are indeed chimpanzees. There are three types of chimps- Pan troglodytes or the common chimpanzee, Pan paniscus or the pygmy chimpanzee, also called the bonobo and Homo sapiens or us.

Note that the DNA relationship is 98.4 per cent and not 100 per cent. This difference of about 1.6per cent can be traced in terms of the time period long ago, when our lineage branched out of the chimpanzees'. Analysis of the time course of such DNA divergence suggests that this happened anywhere between 5.8 to 7.1 million yeas (Myr) ago- that is roughly about 2,00,000 generations ago. Likewise, the divergence between us and the gorilla happened 8.3-10.1 Myr ago.

With molecular data, we can read the chemical sequence of the DNA molecules and estimate our kinship more accurately. Analysis of the gene sequences of the blood protein globin shows 98.76 per cent identity between chimpanzees and humans, and 98.38 per cent between humans and gorillas. We humans are all of the gorilla gotram (lineage or family order), and the two chimps are our cousins with us being (as Dr Jared Diamond has dubbed us) the third chimpanzee. It is truly admirable of Charles Darwin to have been able to propose this evolutionary relationship by analysing not our DNA (he had no idea of the genome, genes or DNA then) but our body features, and using geological evidence as the clock.

While there has been justifiable excitement about the reading of the human genome, it is of considerable relevance to decode the genome of the apes as well. Dr Joseph G. Hacia of the University of Southern California makes a persuasive case for analysing the ape genome in the November 2001 issue of Trends in Genetics. He points out that sequence and chromosomal organisation differences between the human and ape genomes will provide a variety of clues. It can, for example, offer information on the genetic basis behind how we walk on two legs while the gorilla still languorously moves about using his hands as walking aids. It should also give us clues about how we came about to have a more advanced cognitive function. Dr Craig Venter of Celera Genomics, the pioneer of the `private effort' in sequencing the human genome has already committed his group to efforts in sequencing the chimpanzee genome.

It is now realised that the chapters in our genetic book are not just sentences set in a row. They are interspersed quite atrociously with a lot of meaningless gibberish. Often this gibberish even intrudes mid-sentence, so that the reading of a gene or its expression is to be done with some effort. While genes are expressed as proteins or as control switches, and thus `expressed' messages (exons), the intervening gibberish or `junk' DNA does not code any message and is thus a noncoding interruption. Invariably these `introns' are repetitive sequnces of DNA alphabets- single letters, doublets, triplets or phrases. There are millions of these in the human genome (about 45 per cent of the entire length is junk!). The ape genome also seems to have such long repeat elements by the million. A study of their relative lengths and abundance offers us some insight into the process of evolution from the primate to the human.

In addition to these, there occur in both the human and ape genomes, sequences called pseudogenes. These are not expressed as functional proteins or controls, but carried along as vestiges along the path of evolution. They are thus nonfunctional. A whole class of these has to do with the sense of smell. A monkey, a chimpanzee and certainly we humans no longer have the same acute sense of smell that a dog or a mouse has- both in terms of sensitivity and spectrum of detection. These pseudogenes are highest in the human genome and next in the chimps, while the New World monkeys have none at all. Here then is a clue to when the simian branch evolved and diverged from the primate line. To paraphrase Prime Minister Narasimha Rao who said "No action is also action", no expression is also an indication of the path of genetics. As other cognitive functions develop, reduction or loss of one sensory function is not life-threatening. Hence in the course of evolution, mutations deprive you some and offer you something else. The set of mutations that altered the morphology of the palm as to produce the opposing thumb, for example, led to major physiological and behavioural changes in the chimps and humans. This seemingly minor genetic change has allowed them to make tools.

If the chimpanzees and humans have almost 99 per cent genomic identity, why do we not use the body parts of chimps for transplanting to needy humans? Or, can they interbreed so as to produce a mule-like species- Homo troglodytes (or human zee), Pan sapiens (or chi man) or whatever the hybrid is to be called? Interbreeding or exchange of body parts can be allowed only if the genes that code for the proteins which help in the recognition of "foreign" or "non-self" are compatible. Even if there is a minor variation in these gene clusters, "foreignness" is recognised and the body defences are commandeered into action. This group of genes goes by the names of MHC classes I and II. We need to study the differences between the MHC complexes of apes and humans. Comparisons made, based on currently available gene sequences, have not made us wiser so far.

Sometimes, tiny glitches in the gene sequence can have remarkable effects. Professor Ajit Varki, a San Diego biologist of Indian origin, has been able to look at the consequences of one such glitch in the gene sequences of an enzyme called CMP-sialic acid hydroxylase between man and the great apes. This enzyme helps in putting a molecular `recognition flag', called Neu5Glc, on the surface of practically every cell in the body. Varki found that, unlike the apes, we humans do not produce this magic molecule. We make a slight variant called Neu5Ac (which misses a single oxygen atom at a crucial part of the molecule). The consequence of this minor difference to the physiological response is enormous. For example, this seems to account for why organ transplants from chimpanzee to man fails. It also seems to be responsible for why the AIDS virus attacks the two species differently, or why chimpanzees resist malarial infection better than humans. The modification in this enzyme also seems to remove all traces of Neu5Glc from the human brain, substituting it with Neu5Ac. A Japanese group is trying to genetically engineer mice, removing the gene for making Neu5Glc and putting in that, which helps make Neu5Ac instead. What these chimeric mice will do is an open question. Dr Varki is reported to remark wryly: "maybe their mice will speak"!

As Dr. Hacia remarks in his review in Trends in Genetics, "Although biomedical research will benefit from a study of the ape genome, we should also contemplate how chimpanzees and gorillas could benefit from discoveries derived from the use of their DNA, cells and tissues.

A greater scientific awareness that wild ape populations are valuable genetic resources could help increase funding for conservation projects. A community effort is needed to foster open dialogue among scientists and the general public... about our societal responsibilities towards preserving these species".

D. Balasubramanian

L. V. Prasad Eye Institute

Hyderabad 500034

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