Initial sequencing and analysis of the human genome - Vitagenes

articlesDNA transposons (Fig. 24). However, this effect seems too slow andtoo small to account for the observed remodelling of the Aludistribution. This can be seen by performing a similar analysis forLINE elements (Fig. 25). There is no signi®cant change in the LINEdistribution over the past 100 Myr, in contrast to the rapid changeseen for Alu. There is an eventual shift after more than 100 Myr,although its magnitude is still smaller than seen for Alus.These observations indicate that there may be some force actingparticularly on Alus. This could be a higher rate of random loss ofAlus in AT-rich DNA, negative selection against Alus in AT-richDNA or positive selection in favour of Alus in GC-rich DNA.The ®rst two possibilities seem unlikely because AT-rich DNA isFrequency of L1 class relative to itsaverage density in the genome2.01.81.61.41.21.00.80.60.40.20.052gene-poor and tolerates the accumulation of other transposableelements. The third seems more feasible, in that it involves selectingin favour of the minority of Alus in GC-rich regions rather thanagainst the majority that lie in AT-rich regions. But positiveselection for Alus in GC-rich regions would imply that they bene®tthe organism.Schmid 180 has proposed such a function for SINEs. This hypothesisis based on the observation that in many species SINEs aretranscribed under conditions of stress, and the resulting RNAsspeci®cally bind a particular protein kinase (PKR) and block itsability to inhibit protein translation 181±183 . SINE RNAs would thuspromote protein translation under stress. SINE RNA may be wellsuited to such a role in regulating protein translation, because it canbe quickly transcribed in large quantities from thousands ofelements and it can function without protein translation. Underthis theory, there could be positive selection for SINEs in readilytranscribed open chromatin such as is found near genes. This couldexplain the retention of Alus in gene-rich GC-rich regions. It is alsoconsistent with the observation that SINE density in AT-rich DNA ishigher near genes 142 .Further insight about Alus comes from the relationship betweenAlu density and GC content on individual chromosomes (Fig. 26).There are two outliers. Chromosome 19 is even richer in Alus thanpredicted by its (high) GC content; the chromosome comprises 2%of the genome, but contains 5% of Alus. On the other hand,chromosome Y shows the lowest density of Alus relative to its GCcontent, being higher than average for GC content less than 40%and lower than average for GC content over 40%. Even in AT-richDNA, Alus are under-represented on chromosome Y comparedwith other young interspersed repeats (see below). These phenomenamay be related to an unusually high gene density on chromosome19 and an unusually low density of somatically active genes onchromosome Y (both relative to GC content). This would beconsistent with the idea that Alu correlates not with GC contentbut with actively transcribed genes.Our results may support the controversial idea that SINEsactually earn their keep in the genome. Clearly, much additionalwork will be needed to prove or disprove the hypothesis that SINEsare genomic symbionts.Biases in human mutation. Indirect studies have suggestedthat nucleotide substitution is not uniform across mammalianProportion comprised by Alu0.350.300.250.200.150.100.05052GC content bins (%)Chr1Chr2Chr3Chr4Chr5Chr6Chr7Chr8Chr9Chr10Chr11Chr12Chr13Chr14Chr15Chr16Chr17Chr18Chr19Chr20Chr21Chr22ChrXChrYFigure 26 Comparison of the Alu density of each chromosome as a function of local GCcontent. At higher GC levels, the Alu density varies widely between chromosomes, withchromosome 19 being a particular outlier. In contrast, the LINE1 density pattern is quiteuniform for most chromosomes, with the exception of a 1.5 to 2-fold over-representationin AT-rich regions of the X and Y chromosomes (not shown).NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com © 2001 Macmillan Magazines Ltd885