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The number of coding genes in the human genome is still under debate [1]. Here, we present a proposal to define the human reference gene set that takes into account the inter-individual differences in gene numbers arising from gene inactivation events, such as premature termination or aberrant splicing due to nonsense SNPs or SNPs at essential splice sites respectively. We have analyzed SNPs (specifically nonsense SNPs and SNPs affecting essential splice sites) from 23 personal genomes and exomes. We see a wide range in numbers of SNPs in each of the categories surveyed. A large fraction of these SNPs are singletons. Using a data set of high-confidence SNPs obtained by intersecting SNPs from dbSNP and the personal genomes, we identify a common set of 279 genes predicted to be pseudogenic (non-functional) in some individuals and functional in others. We focused on two key questions arising from these considerations: (i) Which criteria should be used for inclusion and exclusion of genes from the reference set? (ii) What sequence should be used as the reference for genes that are non-functional in some humans? For the first question, we propose to include all genes that are functional even in one individual to produce a maximally-inclusive set of genes. For the second, we propose the use of the ancestral allele as the reference allele. This will provide a uniform basis for gene annotation and ensure that the reference gene set and sequence will be relatively stable as more individual genomes are sequenced. In the few cases where an ancestral state assignment is unavailable or ambiguous, we propose that genes be annotated as the functional allele.

An analysis of ribosomal protein pseudogenes in the four mammalian genomes reveals no correlation between number of pseudogenes and mRNA abundance., Background The availability of genome sequences of numerous organisms allows comparative study of pseudogenes in syntenic regions. Conservation of pseudogenes suggests that they might have a functional role in some instances. Results We report the first large-scale comparative analysis of ribosomal protein pseudogenes in four mammalian genomes (human, chimpanzee, mouse and rat). To this end, we have assigned these pseudogenes in the four organisms using an automated pipeline and make the results available online. Each organism has a large number of ribosomal protein pseudogenes (approximately 1,400 to 2,800). The majority of them are processed (generated by retrotransposition). However, we do not see a correlation between the number of pseudogenes associated with a ribosomal protein gene and its mRNA abundance. Analysis of pseudogenes in syntenic regions between species shows that most are conserved between human and chimpanzee, but very few are conserved between primates and rodents. Interestingly, syntenic pseudogenes have a lower rate of nucleotide substitution than their surrounding intergenic DNA. Moreover, evidence from expressed sequence tags indicates that two pseudogenes conserved between human and mouse are transcribed. Detailed analysis shows that one of them, the pseudogene of RPS27, is likely to be a protein-coding gene. This is significant as previous reports indicated there are exactly 80 ribosomal protein genes encoded by the human genome. Conclusions Our analysis indicates that processed ribosomal protein pseudogenes abound in mammalian genomes, but few of these are conserved between primates and rodents. This highlights the large amount of recent retrotranspositional activity in mammals and a relatively larger amount of it in the rodent lineage.