Initial sequencing and analysis of the human genome - Vitagenes

articlesThe most extreme mechanism is whole-genome duplication(WGD), through a polyploidization event in which a diploidorganism becomes tetraploid. Such events are classi®ed as autopolyploidyor allopolyploidy, depending on whether they involvehybridization between members of the same species or differentspecies. Polyploidization is common in the plant kingdom, withmany known examples among wild and domesticated crop species.Alfalfa (Medicago sativa) is a naturally occurring autotetraploid 364 ,and Nicotiana tabacum, some species of cotton (Gossypium) andseveral of the common brassicas are allotetraploids containing pairsof `homeologous' chromosome pairs.In principle, WGD provides the raw material for great bursts ofinnovation by allowing the duplication and divergence of entirepathways. Ohno 365 suggested that WGD has played a key role inevolution. There is evidence for an ancient WGD event in theancestry of yeast and several independent such events in the ancestryof mustard weed 366±369 . Such ancient WGD events can be hard todetect because only a minority of the duplicated loci may beretained, with the result that the genes in duplicated segmentscannot be aligned in a one-to-one correspondence but ratherrequire many gaps. In addition, duplicated segments may besubsequently rearranged. For example, the ancient duplication inthe yeast genome appears to have been followed by loss of more than90% of the newly duplicated genes 366 .One of the most controversial hypotheses about vertebrateevolution is the proposal that two WGD events occurred early inthe vertebrate lineage, around the time of jawed ®shes some 500 Myrago. Some authors 370±373 have seen support for this theory in the factthat many human genes occur in sets of four homologuesÐmostnotably the four extensive HOX gene clusters on chromosomes 2, 7,12 and 17, whose duplication dates to around the correct time.However, other authors have disputed this interpretation 374 ,suggesting that these cases may re¯ect unrelated duplications ofspeci®c regions rather than successive WGD.We analysed the draft genome sequence for evidence that mightbear on this question. The analysis provides many interestingobservations, but no convincing evidence of ancient WGD. Welooked for evidence of pairs of chromosomal regions containingmany homologous genes. Although we found many pairs containinga few homologous genes, the human genome does not appear tocontain any pairs of regions where the density of duplicated genesapproaches the densities seen in yeast or mustard weed 366±369 .We also examined human proteins in the IPI for which theorthologues among ¯y or worm proteins occur in the ratios 2:1:1,3:1:1, 4:1:1 and so on (Fig. 49). The number of such families fallssmoothly, with no peak at four and some instances of ®ve or morehomologues. Although this does not rule out two rounds of WGDfollowed by extensive gene loss and some unrelated gene duplication,it provides no support for the theory. More probatively, if twosuccessive rounds of genome duplication occurred, phylogeneticanalysis of the proteins having 4:1:1 ratios between human, ¯y andworm would be expected to show more trees with the topology(A,B)(C,D) for the human sequences than (A,(B,(C,D))) 375 .However,of 57 sets studied carefully, only 24% of the trees constructedfrom the 4:1:1 set have the former topology; this is not signi®cantlydifferent from what would be expected under the hypothesis ofrandom sequential duplication of individual loci.100Occurrences101 2 3 4 5 6 7 8 9 10 11 12100 10 20 30 40 50 60 70 80 90 100Genes per conserved segmentFigure 47 Distribution of number of genes per conserved segment between human andmouse genomes.10013 14 15 16 17 18 19 20 21 22 X Y1 2 3 4 5 6 7 8 9 10Occurrences1011 12 13 14 15 16 17 18 19 X YFigure 46 Conserved segments in the human and mouse genome. Humanchromosomes, with segments containing at least two genes whose order is conserved inthe mouse genome as colour blocks. Each colour corresponds to a particular mousechromosome. Centromeres, subcentromeric heterochromatin of chromosomes 1, 9 and16, and the repetitive short arms of 13, 14, 15, 21 and 22 are in black.105 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90Conserved segment length (Mb)Figure 48 Distribution of lengths (in 5-Mb bins) of conserved segments between humanand mouse genomes, omitting singletons.910 © 2001 Macmillan Magazines Ltd NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com