Significant Transmission Ratio Distortion Research Articles

Unravelling transmission ratio distortion across the bovine genome: identification of candidate regions for reproduction defects

BackgroundBiological mechanisms affecting gametogenesis, embryo development and postnatal viability have the potential to alter Mendelian inheritance expectations resulting in observable transmission ratio distortion (TRD). Although the discovery of TRD cases have been around for a long time, the current widespread and growing use of DNA technologies in the livestock industry provides a valuable resource of large genomic data with parent–offspring genotyped trios, enabling the implementation of TRD approach. In this research, the objective is to investigate TRD using SNP-by-SNP and sliding windows approaches on 441,802 genotyped Holstein cattle and 132,991 (or 47,910 phased) autosomal SNPs.ResultsThe TRD was characterized using allelic and genotypic parameterizations. Across the whole genome a total of 604 chromosomal regions showed strong significant TRD. Most (85%) of the regions presented an allelic TRD pattern with an under-representation (reduced viability) of carrier (heterozygous) offspring or with the complete or quasi-complete absence (lethality) for homozygous individuals. On the other hand, the remaining regions with genotypic TRD patterns exhibited the classical recessive inheritance or either an excess or deficiency of heterozygote offspring. Among them, the number of most relevant novel regions with strong allelic and recessive TRD patterns were 10 and 5, respectively. In addition, functional analyses revealed candidate genes regulating key biological processes associated with embryonic development and survival, DNA repair and meiotic processes, among others, providing additional biological evidence of TRD findings.ConclusionsOur results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre- and post-natal viability were also identified, providing opportunities for improving breeding success in cattle.

Whole-genome resequencing reveals loci with allelic transmission ratio distortion in F1 chicken population.

Allelic transmission ratio distortion (TRD) is the significant deviation from the expected ratio under Mendelian inheritance theory, which may be resulted from multiple disrupted biological processes, including germline selection, meiotic drive, gametic competition, imprint error, and embryo lethality. However, it is less known that whether or what extent the allelic TRD is present in farm animals. In this study, whole-genome resequencing technology was applied to reveal TRD loci in chicken by constructing a full-sib F1 hybrid population. Through the whole-genome resequencing data of two parents (30×) and 38 offspring (5×), we detected a total of 2850 TRD SNPs (p-adj < 0.05) located within 400 genes showing TRD, and all of them were unevenly distributed on macrochromosomes and microchromosomes. Our findings suggested that TRD in the chicken chromosome 16 might play an important role in chicken immunity and disease resistance and the MYH1F with significant TRD and allele-specific expression could play a key role in the fast muscle development. In addition, functional enrichment analyses revealed that many genes (e.g., TGFBR2, TGFBR3, NOTCH1, and NCOA1) with TRD were found in the significantly enriched biological process and InterPro terms in relation to embryonic lethality and germline selection. Our results suggested that TRD is considerably prevalent in the chicken genome and has functional implications.

The genomic bases of morphological divergence and reproductive isolation driven by ecological speciation in Senecio (Asteraceae).

Ecological speciation, driven by adaptation to contrasting environments, provides an attractive opportunity to study the formation of distinct species, and the role of selection and genomic divergence in this process. Here, we focus on a particularly clear-cut case of ecological speciation to reveal the genomic bases of reproductive isolation and morphological differences between closely related Senecio species, whose recent divergence within the last ~200,000 years was likely driven by the uplift of Mt. Etna (Sicily). These species form a hybrid zone, yet remain morphologically and ecologically distinct, despite active gene exchange. Here, we report a high-density genetic map of the Senecio genome and map hybrid breakdown to one large and several small quantitative trait loci (QTL). Loci under diversifying selection cluster in three 5 cM regions which are characterized by a significant increase in relative (F(ST)), but not absolute (d(XY)), interspecific differentiation. They also correspond to some of the regions of greatest marker density, possibly corresponding to 'cold-spots' of recombination, such as centromeres or chromosomal inversions. Morphological QTL for leaf and floral traits overlap these clusters. We also detected three genomic regions with significant transmission ratio distortion (TRD), possibly indicating accumulation of intrinsic genetic incompatibilities between these recently diverged species. One of the TRD regions overlapped with a cluster of high species differentiation, and another overlaps the large QTL for hybrid breakdown, indicating that divergence of these species may have occurred due to a complex interplay of ecological divergence and accumulation of intrinsic genetic incompatibilities.

Interspecific crossing and genetic mapping reveal intrinsic genomic incompatibility between two Senecio species that form a hybrid zone on Mount Etna, Sicily

Studies of hybridizing species can reveal much about the genetic basis and maintenance of species divergence in the face of gene flow. Here we report a genetic segregation and linkage analysis conducted on F2 progeny of a reciprocal cross between Senecio aethnensis and S. chrysanthemifolius that form a hybrid zone on Mount Etna, Sicily, aimed at determining the genetic basis of intrinsic hybrid barriers between them. Significant transmission ratio distortion (TRD) was detected at 34 (∼27%) of 127 marker loci located in nine distinct clusters across seven of the ten linkage groups detected, indicating genomic incompatibility between the species. TRD at these loci could not be attributed entirely to post-zygotic selective loss of F2 individuals that failed to germinate or flower (16.7%). At four loci tests indicated that pre-zygotic events, such as meiotic drive in F1 parents or gametophytic selection, contributed to TRD. Additional tests revealed that cytonuclear incompatibility contributed to TRD at five loci, Bateson-Dobzhansky-Muller (BDM) incompatibilities involving epistatic interactions between loci contributed to TRD at four loci, and underdominance (heterozygote disadvantage) was a possible cause of TRD at one locus. Major chromosomal rearrangements were probably not a cause of interspecific incompatibility at the scale that could be examined with current map marker density. Intrinsic genomic incompatibility between S. aethnensis and S. chrysanthemifolius revealed by TRD across multiple genomic regions in early-generation hybrids is likely to impact the genetic structure of the natural hybrid zone on Mount Etna by limiting introgression and promoting divergence across the genome.

The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population

The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

Relationship between transmission ratio distortion and genetic divergence in intraspecific rice crosses

The strength of reproductive isolation often correlates positively with parental divergence in both animals and plants. Here, we assess the relationship between transmission ratio distortion (TRD) of marker loci and parental divergence in intraspecific rice (Oryza sativa L.) crosses. We produced 10 diverse F(2) populations by crossing a temperate japonica reference accession with each of 10 donor accessions belonging to subpopulations different from the reference accession, and then genotyped the F(2) populations using molecular markers distributed across the entire genome. Significant TRDs (α=0.05) were detected in 9 of the 10 F(2) populations. TRD regions on chromosomes 3 and 6 were common to several populations; in contrast, other TRD regions were unique to a single population, indicating the diversification of genomic location of TRDs among the populations. The level of TRD (estimated from the overall number and magnitude of TRDs) was significantly correlated with the genetic distance between the donor accessions and the reference accession. Our results suggest that in intraspecific rice crosses, parental divergence may result in diversification of the TRD pattern, followed by an increase in the level of TRD.

Segregation distortion in chicken and the evolutionary consequences of female meiotic drive in birds

As all four meiotic products give rise to sperm in males, female meiosis result in a single egg in most eukaryotes. Any genetic element with the potential to influence chromosome segregation, so that it is preferentially included in the egg, should therefore gain a transmission advantage; a process termed female meiotic drive. We are aware of two chromosomal components, centromeres and telomeres, which share the potential to influence chromosome movement during meioses and make the following predictions based on the presence of female meiotic drive: (1) centromere-binding proteins should experience rapid evolution as a result of a conflict between driving centromeres and the rest of the genome; and (2) segregation patterns should be skewed near centromeres and telomeres. To test these predictions, we first analyze the molecular evolution of seven centromere-binding proteins in nine divergent bird species. We find strong evidence for positive selection in two genes, lending support to the genomic conflict hypothesis. Then, to directly test for the presence of segregation distortion, we also investigate the transmission of approximately 9000 single-nucleotide polymorphisms in 197 chicken families. By simulating fair Mendelian meioses, we locate chromosomal regions with statistically significant transmission ratio distortion. One region is located near the centromere on chromosome 1 and a second region is located near the telomere on the p-arm of chromosome 1. Although these observations do not provide conclusive evidence in favour of the meiotic drive/genome conflict hypothesis, they do lend support to the hypothesis that centromeres and telomeres drive during female meioses in chicken.

Evidence of subtle departures from Mendelian segregation in a wild lesser kestrel (Falco naumanni) population

Some alleles are inherited more frequently than expected from Mendel's rule. This phenomenon, known as transmission ratio distortion (TRD), is found in a broad variety of taxa, but it is thought to be unusual and occurs at a low frequency in any particular population. Here, we used seven microsatellite markers to search for possible TRD in a wild lesser kestrel (Falco naumanni) population. Among the nine alleles analysed with at least 200 known meioses for each sex, we found that two of them (156-AG5 in males and 362-FN1.11 in females) presented subtle (k=0.6) but significant departures from Mendelian segregation. Moreover, in a sample of 53 alleles with at least 15 known meioses, we found a positive correlation between their transmission rates and their frequencies in the population. To estimate the transmission scores for the loci and individuals, we developed a method that allowed us to discover that another locus, FP-46, showed significant TRD, despite the lack of a significant deviation from parity for the alleles considered individually. Finally, we found a consistent transmission bias both within loci and within individuals across loci. Inter-individual differences in TRD support the idea that distorters act over several loci that are evenly distributed across the whole genome, particularly in individuals bearing the distorter alleles. Overall, these findings suggest that TRD might be a more widespread phenomenon than previously revealed by analyses at the allele level.

A novel sampling design to explore gene-longevity associations: the ECHA study

To investigate the genetic contribution to familial similarity in longevity, we set up a novel experimental design where cousin-pairs born from siblings who were concordant or discordant for the longevity trait were analyzed. To check this design, two chromosomal regions already known to encompass longevity-related genes were examined: 6p21.3 (genes TNFalpha, TNFbeta, HSP70.1) and 11p15.5 (genes SIRT3, HRAS1, IGF2, INS, TH). Population pools of 1.6, 2.3 and 2.0 million inhabitants were screened, respectively, in Denmark, France and Italy to identify families matching the design requirements. A total of 234 trios composed by one centenarian, his/her child and a child of his/her concordant or discordant sib were collected. By using population-specific allele frequencies, we reconstructed haplotype phase and estimated the likelihood of Identical By Descent (IBD) haplotype sharing in cousin-pairs born from concordant and discordant siblings. In addition, we analyzed haplotype transmission from centenarians to offspring, and a statistically significant Transmission Ratio Distortion (TRD) was observed for both chromosomal regions in the discordant families (P=0.007 for 6p21.3 and P=0.015 for 11p15.5). In concordant families, a marginally significant TRD was observed at 6p21.3 only (P=0.06). Although no significant difference emerged between the two groups of cousin-pairs, our study gave new insights on the hindrances to recruiting a suitable sample to obtain significant IBD data on longevity-related chromosomal regions. This will allow to dimension future sampling campaigns to study-genetic basis of human longevity.

A microsatellite-based genetic linkage map of the waterflea, Daphnia pulex: On the prospect of crustacean genomics

We describe the first genetic linkage map for Daphnia pulex using 185 microsatellite markers, including 115 new markers reported in this study. Our approach was to study the segregation of polymorphisms in 129 F 2 progeny of one F 1 hybrid obtained by crossing two genetically divergent lineages of Daphnia isolated from two Oregon populations. The map spanned 1206 Kosambi cM and had an average intermarker distance of 7 cM. Linkage groups ranged in size from 7 to 185 cM and contained 4 to 27 markers. The map revealed 12 linkage groups corresponding to the expected number of chromosomes and covers approximately 87% of the genome. Tests for random segregation of alleles at individual loci revealed that 21% of the markers showed significant transmission ratio distortion (primarily homozygote deficiency) likely due to markers being linked to deleterious recessive alleles. This map will become the anchor for the physical map of the Daphnia genome and will serve as a starting point for mapping single and quantitative trait loci affecting ecologically important phenotypes. By mapping 342 tentative orthologous gene pairs ( Daphnia/ Drosophila) into the Daphnia linkage map, we facilitate future comparative projects.

A genetic linkage map ofSilene vulgarisbased on AFLP markers

A genetic linkage map of an intraspecific cross between 2 Silene vulgaris s.l. ecotypes is presented. Three-hundred AFLP markers from 2 different restriction enzyme combinations were used to genotype an F2 mapping population. Maternal and paternal pure-coupling phase maps with 114 and 186 markers on 12 and 13 linkage groups, respectively, were constructed. Total map length of the paternal and maternal maps are 547 and 446 Kosambi cM, respectively. Nearly half of the markers (49%) exhibited significant transmission ratio distortion. Genome coverage and potential causes of the observed segregation ratio distortions are discussed. The maps represent a first step towards the identification of quantitative trait loci associated with habitat adaptation in the non-model species Silene vulgaris.

Genome-Wide Associations Between Hybrid Sterility QTL and Marker Transmission Ratio Distortion

Marker transmission ratio distortion (TRD) in genetic mapping populations is frequently ascribed to selection against allelic combinations that cause hybrid incompatibility. Accordingly, genomic regions of TRD should be nonrandomly associated (colocated) with loci that underlie hybrid incompatibility. To directly test this hypothesis, we evaluated the genome-wide qualitative and quantitative agreement between chromosomal regions exhibiting marker TRD and those known to contain hybrid incompatibility quantitative trait locus (QTL). Incompatibility data came from a near-isogenic line (NIL) analysis of pollen and seed sterility in a cross between two Solanum (formerly Lycopersicon) species. We assessed (1) whether these incompatibility loci are colocated with markers that show significant TRD in two earlier generations preceding these introgression lines and (2) whether the magnitude of marker distortion quantitatively matches the estimated strength of selection against each incompatibility locus. We found evidence that TRD regions are chromosomally colocated with hybrid incompatibility loci more frequently than is expected by chance: pollen sterility QTLs were most closely associated with distorted heterozygote frequencies in later-generation backcrosses. Nonetheless, there was no evidence for an association between TRD and seed sterility and little evidence of a quantitative association between the magnitude of marker TRD and the fitness effects of heterospecific alleles at each chromosomal location. We propose and test a model (the "dance partner" model) to explain several cases where regions of TRD are not associated with hybrid incompatibility loci. Under this model, some NILs containing greater than one heterospecific introgression may not express hybrid incompatibility phenotypes because they carry both appropriate genetic dance partners required for a fully functional interaction. Accordingly, negative interactions expressed in earlier backcross generations are masked in these double-introgression NILs. Based on this model, we identify the location of several new putative pairwise interactors underlying hybrid incompatibility in this species cross.

Transmission ratio distortion in the myotonic dystrophy locus in human preimplantation embryos

One form of myotonic dystrophy, dystrophia myotonica 1 (DM1), is caused by the expansion of a (CTG)(n) repeat within the dystrophia myotonica-protein kinase (DMPK) gene located in chromosome region 19q13.3. Unaffected individuals carry alleles with repeat size (CTG)(5-37), premutation carriers (CTG)(38-49) and DM1 affected individuals (CTG)(50-6,000). Preferential transmission both of expanded repeats from DM1-affected parents and larger DMPK alleles in the normal-size range have been reported in live-born offspring. To determine the moment in development when transmission ratio distortion (TRD) for larger normal-size DMPK alleles is generated, the transmission from heterozygous parents with one repeat within the (CTG)(5-18) range (Group I repeat) and the other within the (CTG)(19-37) range (Group II repeat) to human preimplantation embryos was analysed. A statistically significant TRD of 59% (95% confidence interval of 54-64) in favour of Group II repeats from both mothers and fathers was observed in preimplantation embryos, which remained significant when female embryos were considered separately. In contrast, no significant TRD was detected for repeats from informative Group I/Group I parents. Our analysis showed that Group II repeats specifically were preferentially transmitted in human preimplantation embryos. We suggest that TRD, in Group II repeats at the DMPK locus, is likely to result from events occurring at or around the time of fertilisation.

Sperm dysfunction in the Rb(6.16)‐ and Rb(6.15)‐bearing mice revisited: Involvement of Hyalp1 and Hyal5

Earlier we showed that Sperm adhesion molecule1 (Spam1), the best studied sperm hyaluronidase, is involved in the sperm dysfunction associated with Robertsonian translocations (Rb). The dysfunction results in reduced fertility in mice homozygous for the Rb(6.16) or the Rb(6.15) translocation and transmission ratio distortion (TRD) in heterozygous males. This conclusion was based on the finding that Spam1 in the Rbs harbors multiple point mutations and a genomic alteration at the locus [in the case of Rb(6.16)]; and is accompanied by reduced steady-state levels of the RNA and protein. Here we show that closely linked family members in the hyaluronidase gene cluster on mouse chromosome 6, Hyalp1 and Hyal5, also harbor point mutations in these Rbs, leading to nonconservative substitutions in both the encoded proteins. To test if Spam1 by itself is capable of producing TRD we analyzed the transmission of wild-type and null alleles of the gene in the progeny of carriers and show that there is no significant TRD. This lack of TRD in null carriers argues for only a contributory role of Spam1 in the TRD seen in the Rb-bearing mice, and supports the involvement of Hyalp1 and/or Hyal5 in the sperm dysfunction and the resulting TRD. It is proposed that the clustering of point mutations in all three genes results from the cumulative effect of spontaneous mutations that do not disperse in the population due to suppression of recombination that occurs at Rb junctions.

A genetic map in the Mimulus guttatus species complex reveals transmission ratio distortion due to heterospecific interactions.

As part of a study of the genetics of floral adaptation and speciation in the Mimulus guttatus species complex, we constructed a genetic linkage map of an interspecific cross between M. guttatus and M. nasutus. We genotyped an F(2) mapping population (N = 526) at 255 AFLP, microsatellite, and gene-based markers and derived a framework map through repeated rounds of ordering and marker elimination. The final framework map consists of 174 marker loci on 14 linkage groups with a total map length of 1780 cM Kosambi. Genome length estimates (2011-2096 cM) indicate that this map provides thorough coverage of the hybrid genome, an important consideration for QTL mapping. Nearly half of the markers in the full data set (49%) and on the framework map (48%) exhibited significant transmission ratio distortion (alpha = 0.05). We localized a minimum of 11 transmission ratio distorting loci (TRDLs) throughout the genome, 9 of which generate an excess of M. guttatus alleles and a deficit of M. nasutus alleles. This pattern indicates that the transmission ratio distortion results from particular interactions between the heterospecific genomes and suggests that substantial genetic divergence has occurred between these Mimulus species. We discuss possible causes of the unequal representation of parental genomes in the F(2) generation.