Introduction Advancing whole-genome precision medicine requires understanding how gene expression is altered by genetic variants, especially those that are outside of protein-coding regions. We developed a computational technique that scores how strongly genetic variants alter RNA splicing, a critical step in gene expression whose disruption contributes to many diseases, including cancers and neurological disorders. A genome-wide analysis reveals tens of thousands of variants that alter splicing and are enriched with a wide range of known diseases. Our results provide insight into the genetic basis of spinal muscular atrophy, hereditary nonpolyposis colorectal cancer and autism spectrum disorder. Methods We used machine learning to derive a computational model that takes as input DNA sequences and applies general rules to predict splicing in human tissues. Given a test variant, our model computes a score that predicts how much the variant disrupts splicing. The model was derived in such a way that it can be used to study diverse diseases and disorders, and to determine the consequences of common, rare, and even spontaneous variants. Results Our technique is able to accurately classify disease-causing variants and provides insights into the role of aberrant splicing in disease. We scored over 650,000 DNA variants and found that disease-causing variants have higher scores than common variants and even those associated with disease in genome-wide association studies. Our model predicts substantial and unexpected aberrant splicing due to variants within introns and exons, including those far from the splice site. For example, among intronic variants that are more than 30 nucleotides away from a splice site, known disease variants alter splicing nine times more often than common variants; among missense exonic disease variants, those that least impact protein function are over five times more likely to alter splicing than other variants. Autism has been associated with disrupted splicing in brain regions, so we used our method to score variants detected using whole genome sequencing data from individuals with and without autism. Genes with high scoring variants include many that have been previously linked with autism, as well as new genes with known neurodevelopmental phenotypes. Most of the high scoring variants are intronic and cannot be detected by exome analysis techniques. When we score clinical variants in spinal muscular atrophy and colorectal cancer genes, up to 94% of variants found to disrupt splicing using minigene reporters are correctly classified. Discussion In the context of precision medicine, causal support for variants that is independent of existing studies is greatly needed. Our computational model was trained to predict splicing from DNA sequence alone, without using disease annotations or population data. Consequently, its predictions are independent of and complementary to population data, genome-wide association studies (GWAS), expression-based quantitative trait loci (QTL), and functi...
How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ~350 million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.
correspondence between case reports and fatality data. These data also establish that mortality rates are not affected by epidemic phase 24. Further confirmation of these results is provided by an analysis of the Aberdeen data (N.B.M-B., P.R. and B.T.G., manuscript in preparation). Concerning infection-induced mortality rates, classic work by Butler 24 , Bartlett 25 , Creighton 5 and others indicates significant mortality due to measles and whooping cough during these periods. Estimates of case fatality rates for measles vary widely, from 1-2% in the postwar era up to 46% prewar 14,26,27 , whereas estimates for whooping cough are in the 3-15% range 24. Data analysis These time series contain a substantial annual component and are further complicated by increasing population sizes over the two periods examined. Hence, analyses of the relationship between measles and whooping cough outbreaks were carried out on de-trended data. We used three separate methods. First, Pearson correlation coefficients were estimated for data aggregated over each epidemic year (October to October). Second, we carried out a linear regression of annual counts of measles against whooping cough and used the slope as a measure of synchrony. The results of this technique were qualitatively identical to those of the Pearson correlation, so we present only those. Finally, we also used Wavelet spectra to explore phase differences between filtered time series 28,29. Further information can be found in the Supplementary Information.
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