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Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14.

We previously mapped a gene for severe pediatric gastroesophageal reflux disease ( GERD1) to a 9-cM interval on chromosome 13q14. In this report, we present the results of DNA sequencing and allelic association analyses that were done in an attempt to clone the GERD1 gene. Using a candidate transcript approach, we screened affected individuals for mutations in all transcribed regions of all genes, putative genes, and ESTs identified within the 6.2-Mb GERD1 locus based on alignments with the GenBank cDNA databases. From a total of 50 identifiable genes and 99 EST clusters in the GERD1 locus, we identified 163 polymorphisms (143 SNPs and 20 INDELs) in 21 genes and 37 ESTs. The patterns of inheritance and/or the high population frequencies of all polymorphic alleles identified in this study argued against causative relationships between any of the alleles and the GERD phenotype. Using a subset of 51 SNPs distributed throughout the GERD1 locus, we performed case-control and family (TDT) allelic association analyses on two sets of samples. The case-control study was performed with 73 GERD cases and 93 controls, and the family study was performed using 22 small families. SNP 160 (position 38,925,329 Mb, UCSChg15 map) gave a significant P value prior to multiple test correction in both the case control and family studies, while SNP168 (at 40,442,903 Mb) showed significant association after multiple test correction in the case-control sample, but was uninformative in the family sample. The results suggest that the GERD1 gene might be located near SNP160 or SNP168.

Adult↗

Genomic heterogeneity of background substitutional patterns in Drosophila melanogaster.

Mutation is the underlying force that provides the variation upon which evolutionary forces can act. It is important to understand how mutation rates vary within genomes and how the probabilities of fixation of new mutations vary as well. If substitutional processes across the genome are heterogeneous, then examining patterns of coding sequence evolution without taking these underlying variations into account may be misleading. Here we present the first rigorous test of substitution rate heterogeneity in the Drosophila melanogaster genome using almost 1500 nonfunctional fragments of the transposable element DNAREP1_DM. Not only do our analyses suggest that substitutional patterns in heterochromatic and euchromatic sequences are different, but also they provide support in favor of a recombination-associated substitutional bias toward G and C in this species. The magnitude of this bias is entirely sufficient to explain recombination-associated patterns of codon usage on the autosomes of the D. melanogaster genome. We also document a bias toward lower GC content in the pattern of small insertions and deletions (indels). In addition, the GC content of noncoding DNA in Drosophila is higher than would be predicted on the basis of the pattern of nucleotide substitutions and small indels. However, we argue that the fast turnover of noncoding sequences in Drosophila makes it difficult to assess the importance of the GC biases in nucleotide substitutions and small indels in shaping the base composition of noncoding sequences.

Animals↗

Majority of divergence between closely related DNA samples is due to indels.

It was recently shown that indels are responsible for more than twice as many unmatched nucleotides as are base substitutions between samples of chimpanzee and human DNA. A larger sample has now been examined and the result is similar. The number of indels is approximately 1/12th of the number of base substitutions and the average length of the indels is 36 nt, including indels up to 10 kb. The ratio (R(u)) of unpaired nucleotides attributable to indels to those attributable to substitutions is 3.0 for this 2 million-nt chimp DNA sample compared with human. There is similar evidence of a large value of R(u) for sea urchins from the polymorphism of a sample of Strongylocentrotus purpuratus DNA (R(u) = 3-4). Other work indicates that similarly, per nucleotide affected, large differences are seen for indels in the DNA polymorphism of the plant Arabidopsis thaliana (R(u) = 51). For the insect Drosophila melanogaster a high value of R(u) (4.5) has been determined. For the nematode Caenorhabditis elegans the polymorphism data are incomplete but high values of R(u) are likely. Comparison of two strains of Escherichia coli O157:H7 shows a preponderance of indels. Because these six examples are from very distant systematic groups the implication is that in general, for alignments of closely related DNA, indels are responsible for many more unmatched nucleotides than are base substitutions. Human genetic evidence suggests that indels are a major source of gene defects, indicating that indels are a significant source of evolutionary change.

Animals↗

Comprehensive identification and characterization of diallelic insertion-deletion polymorphisms in 330 human candidate genes.

Despite being the second most frequent type of polymorphism in the genome, diallelic insertion-deletion polymorphisms (indels) have received far less attention in the study of sequence variation. In this report, we describe an approach that can detect indels in the heterozygous state and can comprehensively identify indels in the target sequence. Using this approach, we identified 2393 indels in a set of 330 candidate genes, i.e. an average of seven indels per gene with about two indels per gene being common (minor allele frequency >or=0.1). We compared the population genetic characteristics of indels with substitutions in this data. Our data supported the findings that deletions occur more frequently in the human genome. 5'-UTR and coding regions of the genes showed a significantly lower diversity for indels compared with other regions, suggesting differences in effects of selection on indels and substitutions. Sequence diversity and pairwise linkage disequilibrium (LD) findings of the different populations were similar to earlier results and included a greater skew towards low-frequency variants and a faster rate of LD decay in the African-descent population compared with the non-African populations. Within populations, the allele frequency spectra and LD-decay profiles for indels were similar to substitutions. Overall, the findings suggest that, although the mechanisms giving rise to indels may be different from those causing substitutions, the evolutionary histories of indels and substitutions are similar, and that indels can play a valuable role in association studies and marker selection strategies.

5' Untranslated Regions↗

Molecular evolution of insertions and deletion in the chloroplast genome of silene.

Insertions, deletions, and inversions in the chloroplast genome of higher plants have been shown to be extremely useful for resolving phylogenetic relationships both between closely related taxa and among more basal lineages. Introns and intergenic spacers from the chloroplast genome are now increasingly used for phylogenetic and population genetic studies of populations from a single species, and it is therefore interesting to know whether indels can provide useful data and hence increase the power of intraspecific studies. Here, we show that indels in three cpDNA intergenic spacers and one cpDNA intron for two species of Silene evolve at slightly higher rates than base pair substitutions. Repeat indels appear to have the highest rate of evolution and are thus more prone to homoplasy. We show that coded indel data have high information content for phylogenetic analysis, and indels thus provide useful information to infer phylogenetic relationships at the intraspecific level.

Chloroplasts↗

Denaturing gradient gel electrophoresis (DGGE): a rapid and sensitive technique to screen nucleotide sequence variation in populations.

We describe a rapid and sensitive method for the detection of nucleotide sequence variation that can be used for large-scale screening of population markers. Denaturing gradient gel electrophoresis (DGGE) detects sequence variants of amplified fragments by the differences in their melting behavior. DGGE detects most single-base substitutions when carried out on products amplified with a primer to which a GC clamp has been added. Although DGGE has been primarily used for the detection of limited numbers of single-base mutations in disease studies, it offers great potential for use in population analysis of genetic markers with greater levels of sequence variation. The methodology described was developed to identify the number and distribution of MHC class I alpha 1 alleles among chinook salmon (Oncorhynchus tshawytscha) populations. DGGE detects 28 of 31 identified alpha 1 sequences, which differ by between 1 and 16 nucleotides and a two-codon indel. By creating a network of control alleles, 22-23 of the MHC alleles can be resolved rapidly and accurately by a single gel run condition, and 27 alleles can be resolved by two gel run conditions. This techniques has been used in surveys scoring alleles from two MHC markers (class I alpha 1 and alpha 2) in 20,000 individuals of chinook and coho (O. kisutch) salmon. A single person in our laboratory now analyzes 160 salmon from one MHC locus per day with DGGE.

Alleles↗

Automating resequencing-based detection of insertion-deletion polymorphisms.

Structural and insertion-deletion (indel) variants have received considerable recent attention, partly because of their phenotypic consequences. Among these variants, the most common are small indels ( approximately 1-30 bp). Identifying and genotyping indels using sequence traces obtained from diploid samples requires extensive manual review, which makes large-scale studies inconvenient. We report a new algorithm, implemented in available software (PolyPhred version 6.0), to help automate detection and genotyping of indels from sequence traces. The algorithm identifies heterozygous individuals, which permits the discovery of low-frequency indels. It finds 80% of all indel polymorphisms with almost no false positives and finds 97% with a false discovery rate of 10%. Additionally, genotyping accuracy exceeds 99%, and it correctly infers indel length in 96% of the cases. Using this approach, we identify indels in the HapMap ENCODE regions, providing the first report of these polymorphisms in this data set.

Algorithms↗

Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.

Germ-line mutations in the BRCA1 gene predispose affected individuals to breast and ovarian cancer syndromes. In an attempt to systematically analyze a broader spectrum of genetic changes ranging from frequent exon deletions and duplications to amino acid replacements and protein truncations, we isolated and characterized full size BRCA1 homologues from a representative group of non-human primates. Our analysis represents the first comprehensive sequence comparison of primate BRCA1 loci and corresponding proteins. The comparison revealed an unusually high proportion of indels in non-coding DNA. The major force driving evolutionary changes in non-coding BRCA1 sequences was Alu-mediated rearrangements, including Alu transpositions and Alu-associated deletions, indicating that structural instability of this locus may be intrinsic in anthropoids. Analysis of the non-synonymous/synonymous ratio in coding portions of the gene revealed the presence of both conserved and rapidly evolving regions in the BRCA1 protein. Previously, a rapidly evolving region with evidence of positive evolutionary selection in human and chimpanzee had been identified only in exon 11. Here, we show that most of the internal BRCA1 sequence is variable between primates and evolved under positive selection. In contrast, the terminal regions of BRCA1, which encode the RING finger and BRCT domains, experienced negative selection, which left them almost identical between the compared primates. Distribution of the reported missense mutations, but not frameshift and nonsense mutations, is positively correlated with BRCA1 protein conservation. Finally, on the basis of protein sequence conservation, we identified missense changes that are likely to compromise BRCA1 function.

Alu Elements↗

Local mutagenic impact of insertions of LTR retrotransposons on the mouse genome.

Solitary LTR loci are the predominant form of LTR retrotransposons in most eukaryotic genomes. They originate from recombination between the two LTRs of an ancestral retrovirus and are therefore incapable of transposition. Despite this inactivity, they appear to have a substantial impact on the host genome. Here we use the murine RMER10 LTR family as an example to describe how such elements can reshape regions of the genome through multiple mutations on an evolutionary time scale. Specifically, we use phylogenetic analysis of multiple copies of RMER10 in rodent species, as well as comparisons of orthologous pairs in mouse and rat, to argue that insertions of members of this family have locally induced the emergence of tandem repeat loci as well as many indels. Analysis of structural aspects of these sequences (secondary structures and transcription factors signals) may explain why RMER10 can become endogenous "mutagenic" factors through induction of replication fork blockages and/or error-prone repair of aberrant DNA structures. This hypothesis is also consistent with features of other interspersed repeated elements.

Animals↗

Cross-species amplification of soybean (Glycine max) simple sequence repeats (SSRs) within the genus and other legume genera: implications for the transferability of SSRs in plants.

We investigated the transferability of 31 soybean (Glycine max) simple sequence repeat (SSR) loci to wild congeners and to other legume genera. Up to 65% of the soybean primer pairs amplified SSRs within Glycine, but frequently, the SSRs were short and interrupted compared with those of soybeans. Nevertheless, 85% of the loci were polymorphic within G. clandestina. Cross-species amplification outside of the genus was much lower (3%-13%), with polymorphism restricted to one primer pair, AG81. AG81 amplified loci in Glycine, Kennedia, and Vigna (Phaseoleae), Vicia (Vicieae), Trifolium (Trifolieae), and Lupinus (Genisteae) within the Papilionoideae, and in Albizia within the Mimosoideae. The primer conservation at AG81 may be explained by its apparent proximity to the seryl-tRNA synthetase gene. Interspecific differences in allele size at AG81 loci reflected repeat length variation within the SSR region and indels in the flanking region. Alleles of identical size with different underlying sequences (size homoplasy) were observed. Our findings and the emerging patterns in other plant studies suggest that in contrast to animals, successful cross-species amplification of SSRs in plants is largely restricted to congeners or closely related genera. Because mutations in both the SSR region and the flanking region contribute to variation in allele size among species, knowledge of DNA sequence is essential before SSR loci can be meaningfully used to address applied and evolutionary questions.

Base Sequence↗

Analysis of insertions/deletions in protein structures.

An analysis of insertions and deletions (indels) occurring in a databank of multiple sequence alignments based on protein tertiary structure is reported. Indels prefer to be short (1 to 5 residues). The average intervening sequence length between them versus the percentage of residue identity in pairwise alignments shows an exponential behaviour, suggesting a stochastic process such that nearly every loop in an ancestral structure is a possible target for indels during evolution. The results also suggest a limit to the average size of indels accommodated by protein structures. The preferred indel conformations are reverse turn and coil as are the preferred conformations at the indel edges (N- and C-terminal sides). Interruptions in helices and strands were observed as very rare events.

Amino Acid Sequence↗

Comparative genomics of Streptococcus thermophilus phage species supports a modular evolution theory.

The comparative analysis of five completely sequenced Streptococcus thermophilus bacteriophage genomes demonstrated that their diversification was achieved by a combination of DNA recombination events and an accumulation of point mutations. The five phages included lytic and temperate phages, both pac site and cos site, from three distinct geographical areas. The units of genetic exchange were either large, comprising the entire morphogenesis gene cluster, excluding the putative tail fiber genes, or small, consisting of one or maximally two genes or even segments of a gene. Many indels were flanked by DNA repeats. Differences in a single putative tail fiber gene correlated with the host ranges of the phages. The predicted tail fiber protein consisted of highly conserved domains containing conspicuous glycine repeats interspersed with highly variable domains. As in the T-even coliphage adhesins, the glycine-containing domains were recombinational hot spots. Downstream of a highly conserved DNA replication region, all lytic phages showed a short duplication; in three isolates the origin of replication was repeated. The lytic phages could conceivably be derived from the temperate phages by deletion and multiple rearrangement events in the lysogeny module, giving rise to occasional selfish phages that defy the superinfection control systems of the corresponding temperate phages.

Amino Acid Sequence↗

Evolution of transcript structure and base composition of rDNA expansion segment D3 in ticks.

Four to thirty-two copies of the rDNA 28S gene expansion segment D3 and flanking H14 stem were sequenced in six species of ticks (Ixodes: Ixodidae: Acari). Sequence match among species varied from 66% to 97%. Sequence length averaged 130 bases in I. persulcatus across eight Eurasian sites and averaged 186 bases in five other species across 19 Eurasian and North American sites. The difference in length represents one or more deletions totalling about 60 bases that correspond to stems S3 or S4 of the folded transcript. The typical transcript conformation was observed as one possible low energy structure in the five species of longer D3. The structure entails a basal loop with four stem/loop structures, S1-S4 (moving 5' to 3') atop stem H14. A secondary structure lacking S4 but possessing all other putative standard features of the D3 transcript is possible with the shorter I. persulcatus sequences. Interspecific sequence differences occur at higher frequency in loops and bulges vs. complementary pairing regions of stems. Insertion/deletion events (indels) and base substitutions accounted equally for sequence differences. Indels are flanked by similar sequences, suggesting that they occur by slippage during replication. The D3 of Ixodes species is composed of a degenerate set of subrepeats. Thus, unequal exchange among subrepeats may have caused the reduction in length of the I. persulcatus D3. Compensatory base substitution and compensatory insertion/deletion events are indicated by the failure of mutations to affect secondary structure. Transversions accounted for 64% of sequence differences and were biased toward the gain of G and U and the loss of A and C. This bias could re-establish intramolecular base pairing when disrupted by insertions or deletions that shift one side of a stem relative to the other. The distribution of sequence differences, biased substitution, and conservation of transcript conformation in D3 suggest selective constraint.

Animals↗

Pervasive survival of expressed mitochondrial rps14 pseudogenes in grasses and their relatives for 80 million years following three functional transfers to the nucleus.

BACKGROUND: Many mitochondrial genes, especially ribosomal protein genes, have been frequently transferred as functional entities to the nucleus during plant evolution, often by an RNA-mediated process. A notable case of transfer involves the rps14 gene of three grasses (rice, maize, and wheat), which has been relocated to the intron of the nuclear sdh2 gene and which is expressed and targeted to the mitochondrion via alternative splicing and usage of the sdh2 targeting peptide. Although this transfer occurred at least 50 million years ago, i.e., in a common ancestor of these three grasses, it is striking that expressed, nearly intact pseudogenes of rps14 are retained in the mitochondrial genomes of both rice and wheat. To determine how ancient this transfer is, the extent to which mitochondrial rps14 has been retained and is expressed in grasses, and whether other transfers of rps14 have occurred in grasses and their relatives, we investigated the structure, expression, and phylogeny of mitochondrial and nuclear rps14 genes from 32 additional genera of grasses and from 9 other members of the Poales. RESULTS: Filter hybridization experiments showed that rps14 sequences are present in the mitochondrial genomes of all examined Poales except for members of the grass subfamily Panicoideae (to which maize belongs). However, PCR amplification and sequencing revealed that the mitochondrial rps14 genes of all examined grasses (Poaceae), Cyperaceae, and Joinvilleaceae are pseudogenes, with all those from the Poaceae sharing two 4-NT frameshift deletions and all those from the Cyperaceae sharing a 5-NT insertion (only one member of the Joinvilleaceae was examined). cDNA analysis showed that all mitochondrial pseudogenes examined (from all three families) are transcribed, that most are RNA edited, and that surprisingly many of the edits are reverse (U-->C) edits. Putatively nuclear copies of rps14 were isolated from one to several members of each of these three Poales families. Multiple lines of evidence indicate that the nuclear genes are probably the products of three independent transfers. CONCLUSION: The rps14 gene has, most likely, been functionally transferred from the mitochondrion to the nucleus at least three times during the evolution of the Poales. The transfers in Cyperaceae and Poaceae are relatively ancient, occurring in the common ancestor of each family, roughly 80 million years ago, whereas the putative Joinvilleaceae transfer may be the most recent case of functional organelle-to-nucleus transfer yet described in any organism. Remarkably, nearly intact and expressed pseudogenes of rps14 have persisted in the mitochondrial genomes of most lineages of Poaceae and Cyperaceae despite the antiquity of the transfers and of the frameshift and RNA editing mutations that mark the mitochondrial genes as pseudogenes. Such long-term, nearly pervasive survival of expressed, apparent pseudogenes is to our knowledge unparalleled in any genome. Such survival probably reflects a combination of factors, including the short length of rps14, its location immediately downstream of rpl5 in most plants, and low rates of nucleotide substitutions and indels in plant mitochondrial DNAs. Their survival also raises the possibility that these rps14 sequences may not actually be pseudogenes despite their appearance as such. Overall, these findings indicate that intracellular gene transfer may occur even more frequently in angiosperms than already recognized and that pseudogenes in plant mitochondrial genomes can be surprisingly resistant to forces that lead to gene loss and inactivation.

Cell Nucleus↗

Positive selection on nucleotide substitutions and indels in accessory gland proteins of the Drosophila pseudoobscura subgroup.

Genes encoding reproductive proteins often diverge rapidly due to positive selection on nucleotide substitutions. While this general pattern is well established, the extent to which specific reproductive genes experience similar selection in different clades has been little explored, nor have possible targets of positive selection other than nucleotide substitutions, such as indels, received much attention. Here, we inspect for the signature of positive selection in the genes encoding five accessory gland proteins (Acps) (Acp26Aa, Acp32CD, Acp53Ea, Acp62F, and Acp70A) originally described from Drosophila melanogaster but with recognizable orthologues in the D. pseudoobscura subgroup. We compare patterns of selection within the D. psuedoobscura subgroup to those in the D. melanogaster subgroup. Similar patterns of positive selection were found in Acp26Aa and Acp62F in the two subgroups, while Acp53Ea and Acp70A experienced purifying selection in both subgroups. These proteins have thus remained targets for similar types of selection over long (>21-MY) periods of time. We also found several indel substitutions and polymorphisms in Acp26Aa and Acp32CD. These indels occur in the same regions as positively selected nucleotide substitutions for Acp26Aa in the D. pseudoobscura subgroup but not in the D. melanogaster subgroup. Rates of indel substitution within Acp26Aa in the D. pseudoobscura subgroup were up to several times those in noncoding regions of the Drosophila genome. This suggests that indel substitutions may be under positive selection and may play a key role in the divergence of some Acps.

Amino Acid Sequence↗

Haplotype-based systematic association studies of ATP1A2 in migraine with aura.

Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case-control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype-tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender-matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single-marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht-SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.

Adult↗

Genome reduction of the aphid endosymbiont Buchnera aphidicola in a recent evolutionary time scale.

Genome reduction, a typical feature of symbiotic bacteria, was analyzed in the last stages of evolution of Buchnera aphidicola, the primary aphid endosymbiont, in two neutrally evolving regions: the pseudogene cmk and an intergenic region. These two regions were examined in endosymbionts from several lineages of their aphid host Rhopalosiphum padi, and different species of the same genus, whose divergence times ranged from 0.62 to 19.51 million years. Estimates of nucleotide substitution rates were between 4.3 and 6.7x10(-9) substitution/site/year, with G or C nucleotides being substituted around four times more frequently than A or T. Two different types of indel events were detected, of which many were small (1-10 nt) but one was large (about 200 nucleotides). With respect to the large one and considering the proportion and size of the deletions and insertions, the reduction rate was 1.3x10(-8) lost nucleotides/site/year. We propose a stepwise scenario for the last stages of evolution in B. aphidicola: together with a very slow and gradual degradation, considerable indels would punctually emerge. The only restriction to large deletion fixation is that the lost fragment does not contain essential genes.

Animals↗

Selective constraints on intron evolution in Drosophila.

Intron sizes show an asymmetrical distribution in a number of organisms, with a large number of "short" introns clustered around a minimal intron length and a much broader distribution of longer introns. In Drosophila melanogaster, the short intron class is centered around 61 bp. The narrow length distribution suggests that natural selection may play a role in maintaining intron size. A comparison of 15 orthologous introns among species of the D. melanogaster subgroup indicates that, in general, short introns are not under greater DNA sequence or length constraints than long introns. There is a bias toward deletions in all introns (deletion/insertion ratio is 1.66), and the vast majority of indels are of short length (<10 bp). Indels occurring on the internal branches of the phylogenetic tree are significantly longer than those occurring on the terminal branches. These results are consistent with a compensatory model of intron length evolution in which slightly deleterious short deletions are frequently fixed within species by genetic drift, and relatively rare larger insertions that restore intron length are fixed by positive selection. A comparison of paralogous introns shared among duplicated genes suggests that length constraints differ between introns within the same gene. The janusA, janusB, and ocnus genes share two short introns derived from a common ancestor. The first of these introns shows significantly fewer indels than the second intron, although the two introns show a comparable number of substitutions. This indicates that intron-specific selective constraints have been maintained following gene duplication, which preceded the divergence of the D. melanogaster species subgroup.

Animals↗