Conservation of human alternative splice events in mouse

Abstract

Human and mouse genomes share similar long-range sequence organization, and have most of their genes being homologous. As alternative splicing is a frequent and important aspect of gene regulation, it is of interest to assess the level of conservation of alternative splicing. We examined mouse transcript data sets (EST and mRNA) for the presence of transcripts that both make spliced-alignment with the draft mouse genome sequence and demonstrate conservation of human transcript-confirmed alternative and constitutive splice junctions. This revealed 15% of alternative and 67% of constitutive splice junctions as conserved; however, these numbers are patently dependent on the extent of transcript coverage. Transcript coverage of conserved splice patterns is found to correlate well between human and mouse. A model, which extrapolates from observed levels of conservation at increasing levels of transcript support, estimates overall conservation of 61% of alternative and 74% of constitutive splice junctions, albeit with broad confidence intervals. Observed numbers of conserved alternative splicing events agreed with those expected on the basis of the model. Thus, it is apparent that many, and probably most, alternative splicing events are conserved between human and mouse. This, combined with the preservation of alternative frame stop codons in conserved frame breaking events, indicates a high level of commonality in patterns of gene expression between these two species.

Figure 1

Distribution of matched human sequence tags [as constructed by concatenating exon regions that flank an intron (see Materials and Methods)] as per the average nucleotide percent identity (red), amino acid identity (yellow), and amino acid similarity (blue). For each of the tags the given match statistics represent the average over all transcript matches.

Figure 2

Distribution of ESTs to genes in the AltExtron data set of transcript confirmed human introns and exons. The insert shows the distribution with the coverage transformed by log to the base 10. The spike at 100 ESTs represents the sum of all genes with 100 or more aligned ESTs.

Figure 3

The observed level of splice junction conservation as a function of transcript coverage for the constitutive and alternative splice junctions. The final data point of each curve groups all splice junctions with 20 or more human transcripts. Further grouping of data was performed for some of the alternative curve data points, and one of the constitutive curve data points, to allow calculation of sample variance. The grouping was done manually and ensures that each point represents at least 10 human splice junctions. The number of observations at each plotted point is given below as (transcript coverage in human, number of human splice junctions with this coverage value). For the alternative curve: (1, 958), (2, 230), (3, 98), (4, 55), (5, 23), (6, 26), (7, 22), (8–9, 18), (10–14, 12), (15–19, 17) and (20+, 14). For the constitutive curve: (1, 274), (2, 202), (3, 134), (4, 100), (5, 84), (6, 69), (7, 48), (8, 44), (9, 41), (10, 32), (11, 24), (12, 25), (13, 23), (14, 21), (15, 11), (16, 18), (17, 12), (18–19, 20), (20+, 251).