DNA sequence and analysis of human chromosome 18

Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.function ͉ human ͉ isoforms ͉ splice ͉ structure A lternative mRNA splicing, the generation of a diverse range of mature RNAs, has considerable potential to expand the cellular protein repertoire (1-3), and recent studies have estimated that 40-80% of multiexon human genes can produce differently spliced mRNAs (4, 5). The importance of alternative splicing in processes such as development (6) has long been recognized, and proteins coded by alternatively spliced transcripts have been implicated in a number of cellular pathways (7-9). The extent of alternative splicing in eukaryotic genomes has lead to suggestions that alternative splicing is key to understanding how human complexity can be encoded by so few genes (10).The pilot project of the Encyclopedia of DNA Elements (ENCODE) (11), which aims to identify all the functional elements in the human genome, has undertaken a comprehensive analysis of 44 selected regions that make up 1% of the human genome. One valuable element of the project has been the detailing of a reference set of manually annotated splice variants by the GENCODE consortium (12). The annotation by the GENCODE consortium is an extension of the manually curated annotation by the Havana team at The Sanger Institute.Although a full understanding of the functional implications of alternative splicing is still a long way off, the GENCODE set has provided us with the material to make an in-depth assessment of a systematically collected reference set of splice variants. ResultsAlternative Splicing Frequency. The GENCODE set is made up of 2,608 annotated transcripts for 487 distinct loci. A total of 1,097 transcripts from 434 loci are predicted to be protein coding. There are on average 2.53 protein coding variants per locus; 182 loci have only one variant, whereas one locus, RP1-309K20.2 (CPNE1) has 17 coding variants.A total of 57.8% of the loci are annotated with alternatively spliced transcripts, although there are differences between target re...

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“…1a). This number is toward the higher end of previous estimates but in line with the most recent reports (14).…”

Section: Resultssupporting

confidence: 92%

“…1a). This number is toward the higher end of previous estimates but in line with the most recent reports (14).Analysis of the data suggests that the GENCODE-validated transcripts are an underestimate of the real numbers of alter- …”

supporting

confidence: 88%

The implications of alternative splicing in the ENCODE protein complement

Tress

Martelli

Frankish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

201

187

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“…10 This leads us to hypothesize that relatively few genes (ϳ5-10%) will be responsible for the major phenotypic features in a condition like 18q-. There are "officially" only 337 genes on Chromosome 18, 11 so we estimate that only 20 to 30 genes on the entire chromosome will be haploinsufficient. The challenge is to figure out which genes these are.…”

Section: Discussionmentioning

confidence: 91%

A gene dosage map of Chromosome 18: A map with clinical utility

Cody

Carter

Sebold

et al. 2009

Genetics in Medicine

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Purpose: Microarray technology has revolutionized the field of clinical genetics with the ability to detect very small copy number changes. However, challenges remain in linking genotype with phenotype. Our goal is to enable a clinical geneticist to align the molecular karyotype information from an individual patient with the annotated genomic content, so as to provide a clinical prognosis. Methods: We have combined data regarding copy number variations, microdeletion syndromes, and classical chromosome abnormalities, with the sparse but growing knowledge about the biological role of specific genes to create a genomic map of Chromosome 18 with clinical utility. Results: We have created a draft model of such a map, drawing from our longstanding interest in and data regarding the abnormalities of Chromosome 18. Conclusion: We have taken the first step toward creating a genomic map that can be used by the clinician in counseling and directing preventive or symptomatic care of individuals with Chromosome 18 abnormalities. Genet Med 2009:11(11):778 -782.

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“…Interestingly, chromosome 9, which is orthologous to large parts of the chicken Z, is highly structurally polymorphic in humans (Humphray et al, 2004). Trisomies of human 9p (Wilson et al, 1985), and monosomies of 5q and 18q (which all share homology with the chicken Z), survive to birth (Nusbaum et al, 2005;Boultwood et al, 2010). Moreover, the snake Z chromosome is known to share homology with human 3p21-p24, 7p14-p15, 10p11-p15 and 17q21-q24 (Matsubara et al, 2006).…”

Section: Does Dosage Insensitivity Predispose An Autosome To Evolve Smentioning

confidence: 99%

The origin and evolution of vertebrate sex chromosomes and dosage compensation

2011

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In mammals, birds, snakes and many lizards and fish, sex is determined genetically (either male XY heterogamy or female ZW heterogamy), whereas in alligators, and in many reptiles and turtles, the temperature at which eggs are incubated determines sex. Evidently, different sex-determining systems (and sex chromosome pairs) have evolved independently in different vertebrate lineages. Homology shared by Xs and Ys (and Zs and Ws) within species demonstrates that differentiated sex chromosomes were once homologous, and that the sex-specific non-recombining Y (or W) was progressively degraded. Consequently, genes are left in single copy in the heterogametic sex, which results in an imbalance of the dosage of genes on the sex chromosomes between the sexes, and also relative to the autosomes. Dosage compensation has evolved in diverse species to compensate for these dose differences, with the stringency of compensation apparently differing greatly between lineages, perhaps reflecting the concentration of genes on the original autosome pair that required dosage compensation. We discuss the organization and evolution of amniote sex chromosomes, and hypothesize that dosage insensitivity might predispose an autosome to evolving function as a sex chromosome.

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DNA sequence and analysis of human chromosome 18

Cited by 50 publications

References 34 publications

The implications of alternative splicing in the ENCODE protein complement

The implications of alternative splicing in the ENCODE protein complement

A gene dosage map of Chromosome 18: A map with clinical utility

The origin and evolution of vertebrate sex chromosomes and dosage compensation

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