By David N. Leff

One big-bang payoff emerging from the total sequencing of the human genome lays out a strategy for large-scale mapping of human disease genes, plus tracing humanity¿s population history back to its origins.

Fittingly, one of the leaders in the international human genome consortium, human geneticist Eric Lander, is principal propagator of this ambitious program. Lander, director of the Whitehead Institute for Genomic Research in Cambridge, Mass., is senior author of a paper in the current issue of Nature, dated May 10, 2001, which reports this approach. Its title: ¿Linkage disequilibrium in the human genome.¿ The paper¿s first author is population and human geneticist David Reich, a postdoctoral fellow in Lander¿s laboratory.

¿The most powerful technique in current use for disease-gene mapping,¿ Reich told BioWorld Today, ¿is called linkage disequilibrium mapping. LD is an allelic association between two polymorphisms [a condition in which one of two different but normal nucleotide sequences can exist at a particular site in DNA]. So if you have one here, you¿ll find another there. It will predict what you have nearby.

¿LD relies on finding regions of the genome that have identical chromosomal histories across that region. That is, they have particular genetic markers called SNPs, single nucleotide polymorphisms, which mark out that region. SNPs always travel together, because they¿re inherited from a common ancestor, which moved in at some time in the past.

¿So if you have a stretch of a thousand base pairs,¿ Reich explained, ¿and you look at SNPs, which have two sites, two alleles ¿ two nucleotide flavors in adenine and two in cytosine ¿ 20 percent of the gene population is the A, and the rest is the C. Then if you go downstream 5,000 base pairs and find another SNP that¿s also 20 percent and 80 percent, it¿s going to predict what you have at the first one.

¿We found that these regions that track together . . . the reason it¿s important in disease-gene mapping is that if a disease gene occurs on one of them, the mutation is just like a SNP, and it tracks with the other ones nearby. So if you look at the others, they¿ll be good markers for finding that disease gene.¿

Reich cited an example: ¿Say you have 1,000 people with the disease and 1,000 without it, and the gene mutation is at higher frequency in the people with the disease, then the nearby polymorphisms are also going to track with the disease.¿

Harry Potter To The Rescue

Lander proffers an account of LD more at the level of youthful Harry Potter aficionados: ¿To understand this concept,¿ he explained, ¿consider the example of Harry Potter¿s latest book, Goblet of Fire, published in both British and American English editions. Although the two versions tell the exact same story, small spelling differences ¿ color instead of colour ¿ or word choices, such as a car¿s boot¿ vs. the vehicle¿s trunk,¿ enable us to trace the text to the British or American variant. Even if the two versions were shuffled, and differences occurred sporadically within the text, we would be able to tell that pages 7 to 9 came from the British book and 12 to 17 from the American one.

¿Our results, as we reported in Nature,¿ Lander continued, ¿show that the human-history shuffling ¿ at least in the northern European population ¿ has occurred in such a way that the blocks, or stretches, of interspersed text are large enough for us to trace them back to the original edition.¿

Reich described the human DNA experiments he and his co-authors performed to sift the ¿fossil record¿ data in their research:

¿We took a list of regions of the genome where we had previously found a single polymorphism inside a gene, randomized the list and picked 19 regions from it where we had enough contiguous DNA sequence from the Human Genome Project. Each stretch was at least 160,000 base pairs long. Then we sequenced about a quarter of a megabase of DNA from 44 unrelated adult men and women from Utah, of northern European extraction. These volunteers have been very helpful in participating in genetic studies, and providing their DNA samples.

¿We did conventional DNA sequencing, with their DNA samples in water, and used automated computer programs to calculate the distances between these sites and the LD between them. We found linkage disequilibrium extending about eight times further than had been predicted by previous LD searches. This study,¿ Reich pointed out, ¿is different from past LD studies in that it¿s much larger. Past gene hunts have been based on three regions of the genome, this one on 19.

¿The first area that we covered was disease-gene mapping. The results have a major potential for how to find the genes that contribute to common diseases. Our method proved to be practical, whereas there was a worry before that it would be a laborious, impossible task.

¿The other half of the paper,¿ Reich went on, ¿covers results of human population history, based on interpreting the same data. It tells us that a massive population contraction occurred in northern Europeans some time after their divergence from the original African populations.¿

Besides their cohort of 44 Caucasians, the co-authors mobilized DNA from 96 Nigerians.

Fossil DNA¿ Testifies Africans Colonized Europe

¿In our European population,¿ Reich pointed out, ¿we encountered those long stretches of LD we didn¿t expect. In the Africans we found much less. So we surmised that there¿s been no contraction in the history of the African populations compared with the Europeans. But what is interesting is that there was a demographic event of enormous proportions in the divergence of these two populations. That is, a reduction in population size followed by a new expansion about 100,000 years ago ¿ a bottleneck ¿-with more ancestral European founders emerging out of African populations.

¿It¿s well known,¿ Reich recalled, ¿that there was an Out of Africa¿ emigration to Europe as recently as 50,000 years ago. A bottleneck could also be associated with single founders giving rise to the modern European population. This could have happened after the last ice age, which ended as recently as 18,000 years ago in northern Europe. No more than 50 individual survivors out of Africa probably gave rise to most of the modern European gene pool.¿

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