DNA sequence and analysis of human chromosome 9

Abstract

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

Figure 2

The relationship between the physical and deCODE genetic distance. The physical location of each genetic marker is shown on the female, male and sex-averaged genetic maps

Figure 3

Segmental duplications on chromosome 9. a, Intrachromosomal duplications. The top panel shows duplications plotted against the sequence coordinates (matches of >1 kb in length), whereas the bottom panel shows annotated genes on the forward and reverse strand. Some of the gene duplications we identified are also noted. The view is produced using Apollo (http://www.fruitfly.org/annot/apollo). b, Interchromosomal duplications. Large duplications (>10 kb) are shown, with chromosome 9 magnified. Other chromosomes are arranged in the order in which they match to chromosome 9. Chromosomes 8, 14, X and Y are not detected at this level. The grey rectangle is heterochromatin (47–62 Mb). Supplementary Fig. S3 shows interchromosomal duplication matches at >1 kb.

Figure 4

Alignments between duplicated chromosome 9 sequences using MultiPipMaker, indicating percentage identity for each alignment. A genomic duplication event seems to have taken place with a 7,144-bp sequence (5,289,576–5,296,720 bp) and a 7,125-bp region (5,324,724–5,331,849 bp), duplicating the two-exon 5-kb relaxin (RLN) genes. The sequence homology across the duplication shows variation, with the region around the first exon and into the intron matching at 97%, whereas there is a marked decrease in similarity towards exon 2. In comparison, another recently duplicated gene pair, orosomucoid (ORM), duplicated within a 6,212-bp sequence (112,627,806–112,634,018 bp) and 6,220 bp (112,634,577–112,640,797 bp) show more homogeneous sequence alignment.