Human Genome Headlines

• The genomic landscape shows marked variation in the distribution of a number of features, including genes, transposable elements, GC content, CpG islands and recombination rate. This gives us important clues about function. For example, the developmentally important HOX gene clusters are the most repeat-poor regions of the human genome, probably reflecting the very complex coordinate regulation of the genes in the clusters.
• There appear to be about 30,000-40,000 protein-coding genes in the human genome-only about twice as many as in worm or fly. However, the genes are more complex, with more alternative splicing generating a larger number of protein products.
• The full set of proteins (the 'proteome') encoded by the human genome is more complex than those of invertebrates. This is due in part to the presence of vertebrate-specific protein domains and motifs (an estimated 7% of the total), but more to the fact that vertebrates appear to have arranged pre-existing components into a richer collection of domain architectures.
• Hundreds of human genes appear likely to have resulted from horizontal transfer from bacteria at some point in the vertebrate lineage. Dozens of genes appear to have been derived from transposable elements.
• Although about half of the human genome derives from transposable elements, there has been a marked decline in the overall activity of such elements in the hominid lineage. DNA transposons appear to have become completely inactive and long-terminal repeat (LTR) retroposons may also have done so.
• The pericentromeric and subtelomeric regions of chromosomes are filled with large recent segmental duplications of sequence from elsewhere in the genome. Segmental duplication is much more frequent in humans than in yeast, fly or worm.
• Analysis of the organization of Alu elements explains the longstanding mystery of their surprising genomic distribution, and suggests that there may be strong selection in favour of preferential retention of Alu elements in GC-rich regions and that these 'selfish' elements may benefit their human hosts.
• The mutation rate is about twice as high in male as in female meiosis, showing that most mutation occurs in males.
• Cytogenetic analysis of the sequenced clones confirms suggestions that large GC-poor regions are strongly correlated with 'dark G-bands' in karyotypes.
• Recombination rates tend to be much higher in distal regions (around 20 megabases (Mb)) of chromosomes and on shorter chromosome arms in general, in a pattern that promotes the occurrence of at least one crossover per chromosome arm in each meiosis.
• More than 1.4 million single nucleotide polymorphisms (SNPs) in the human genome have been identified. This collection should allow the initiation of genome-wide linkage disequilibrium mapping of the genes in the human population.

Mouse Genome Headlines

• The mouse genome is about 14% smaller than the human genome (2.5 Gb compared with 2.9 Gb). The difference probably reflects a higher rate of deletion in the mouse lineage.
• Over 90% of the mouse and human genomes can be partitioned into corresponding regions of conserved synteny, reflecting segments in which the gene order in the most recent common ancestor has been conserved in both species.
• At the nucleotide level, approximately 40% of the human genome can be aligned to the mouse genome. These sequences seem to represent most of the orthologous sequences that remain in both lineages from the common ancestor, with the rest likely to have been deleted in one or both genomes.
• The neutral substitution rate has been roughly half a nucleotide substitution per site since the divergence of the species, with about twice as many of these substitutions having occurred in the mouse compared with the human lineage.
• By comparing the extent of genome-wide sequence conservation to the neutral rate, the proportion of small (50-100 bp) segments in the mammalian genome that is under (purifying) selection can be estimated to be about 5%. This proportion is much higher than can be explained by protein-coding sequences alone, implying that the genome contains many additional features (such as untranslated regions, regulatory elements, non-protein-coding genes, and chromosomal structural elements) under selection for biological function.
• The mammalian genome is evolving in a non-uniform manner, with various measures of divergence showing substantial variation across the genome.
• The mouse and human genomes each seem to contain about 30,000 protein-coding genes. These refined estimates have been derived from both new evidence-based analyses that produce larger and more complete sets of gene predictions, and new de novo gene predictions that do not rely on previous evidence of transcription or homology. The proportion of mouse genes with a single identifiable orthologue in the human genome seems to be approximately 80%. The proportion of mouse genes without any homologue currently detectable in the human genome (and vice versa) seems to be less than 1%.
• Dozens of local gene family expansions have occurred in the mouse lineage. Most of these seem to involve genes related to reproduction, immunity and olfaction, suggesting that these physiological systems have been the focus of extensive lineage-specific innovation in rodents.
• Mouse-human sequence comparisons allow an estimate of the rate of protein evolution in mammals. Certain classes of secreted proteins implicated in reproduction, host defence and immune response seem to be under positive selection, which drives rapid evolution.
• Despite marked differences in the activity of transposable elements between mouse and human, similar types of repeat sequences have accumulated in the corresponding genomic regions in both species. The correlation is stronger than can be explained simply by local (G+C) content and points to additional factors influencing how the genome is moulded by transposons.
• By additional sequencing in other mouse strains, we have identified about 80,000 single nucleotide polymorphisms (SNPs). The distribution of SNPs reveals that genetic variation among mouse strains occurs in large blocks, mostly reflecting contributions of the two subspecies Mus musculus domesticus and Mus musculus musculus to current laboratory strains.