Autosomal Factor Research Articles

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model.

Sex differences in gene expression are widespread in the liver, where many autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57BL/6J and CAST/EiJ, representing two subspecies separated by 0.5-1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24, Tox, and Zfp809, lose their sex-biased expression in CAST/EiJ mouse liver. To elucidate the observed strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of the sex differences in expression between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-dependent gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs apparently lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.

Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in Diversity Outbred mice.

Sex-specific transcription characterizes hundreds of genes in mouse liver, many implicated in sex-differential drug and lipid metabolism and disease susceptibility. While the regulation of liver sex differences by growth hormone-activated STAT5 is well established, little is known about autosomal genetic factors regulating the sex-specific liver transcriptome. Here we show, using genotyping and expression data from a large population of Diversity Outbred mice, that genetic factors work in tandem with growth hormone to control the individual variability of hundreds of sex-biased genes, including many long non-coding RNA genes. Significant associations between single nucleotide polymorphisms and sex-specific gene expression were identified as expression quantitative trait loci (eQTLs), many of which showed strong sex-dependent associations. Remarkably, autosomal genetic modifiers of sex-specific genes were found to account for more than 200 instances of gain or loss of sex-specificity across eight Diversity Outbred mouse founder strains. Sex-biased STAT5 binding sites and open chromatin regions with strain-specific variants were significantly enriched at eQTL regions regulating correspondingly sex-specific genes, supporting the proposed functional regulatory nature of the eQTL regions identified. Binding of the male-biased, growth hormone-regulated repressor BCL6 was most highly enriched at trans-eQTL regions controlling female-specific genes. Co-regulated gene clusters defined by overlapping eQTLs included sets of highly correlated genes from different chromosomes, further supporting trans-eQTL action. These findings elucidate how an unexpectedly large number of autosomal factors work in tandem with growth hormone signaling pathways to regulate the individual variability associated with sex differences in liver metabolism and disease.

Paircounting

X inactivation presents two longstanding puzzles: the counting and choice of X chromosomes. Here, we consider counting and choice in the context of pairing, both of the X and of the autosomes.

Osteosarcoma inheritance in two families of Scottish deerhounds

BackgroundOsteosarcoma is the most common neoplastic disease in Scottish Deerhounds. For Deerhounds, a 2007 population-based study concluded that a single dominant genetic factor largely governed disease risk. For Greyhounds, Rottweilers, and Irish Wolfhounds, a 2013 genome-wide association study found multiple genetic markers in each breed, with each marker only weakly associated with the disease.We obtained from two breeders the pedigrees, age (if alive) or age at death, and osteosarcoma status for two families of Scottish Deerhounds, designated Cohorts K and T. A dog was considered unaffected only if it was osteosarcoma-free and at least 8.5 years old. We analyzed the data in two ways, by assuming either a single recessive genetic factor or a single dominant genetic factor with high penetrance.ResultsCohort K contained 54 evaluable dogs representing 12 litters. Cohort T contained 56 evaluable dogs representing eight litters. Osteosarcoma seemed clearly heritable in both cohorts; however, having a parent with osteosarcoma raised a pup’s risk of developing osteosarcoma to 38% for Cohort K but 78% for Cohort T, suggesting the possibility of different genetic risk factors in each cohort. In Cohort K, osteosarcoma inheritance fit well with a single, recessive, autosomal risk factor, although we could not rule out the possibility of a single dominant risk factor with incomplete penetrance. In Cohort T, inheritance could be explained well by a single, dominant, autosomal risk factor but was inconsistent with recessive expression.ConclusionsInheritance of osteosarcoma in two Scottish Deerhound families could be explained well by a single genetic risk factor residing on an autosome, consistent with a 2007 report. In one family, inheritance was consistent with dominant expression, as previously reported. In the other family, inheritance fit better with recessive expression, although the possibility of a dominant genetic factor influenced by one or more other genetic factors could not be ruled out. In either case, the results suggest that there may be at least two different genetic risk factors for osteosarcoma in Deerhounds.

A Z-linked sterility locus causes sexual abstinence in hybrid females and facilitates speciation in Spodoptera frugiperda.

In the fall armyworm, Spodoptera frugiperda (Lepidoptera, Noctuidae), two sympatric strains have been recognized that have been termed corn strain (C) and rice strain (R), referring to their most common host plants. Both strains are reproductively isolated via a distinct prezygotic barrier as well as via an intriguing postzygotic phenomenon: when R females have mated with C males, the resulting RC hybrid females exhibit dramatically reduced fertility independent of their mating partner. Here, we demonstrate that the reduced fertility is caused by the fact that these females refrain from mating, that is, females are behaviorally sterile. We identified a Z-chromosomally linked sterility locus that is most likely incompatible with yet to be identified autosomal (or cytoplasmic) factors, leading to the observed sexual abstinence. Within-chromosome mapping revealed the sterility locus to be located in an area of strongly reduced interstrain recombination.

Lineage-Specific Evolution of the Complex Nup160 Hybrid Incompatibility Between Drosophila melanogaster and Its Sister Species.

Two genes encoding protein components of the nuclear pore complex Nup160 and Nup96 cause lethality in F2-like hybrid genotypes between Drosophila simulans and Drosophila melanogaster. In particular, D. simulans Nup160 and Nup96 each cause inviability when hemizygous or homozygous in species hybrids that are also hemizygous (or homozygous) for the D. melanogaster X chromosome. The hybrid lethality of Nup160, however, is genetically complex, depending on one or more unknown additional factors in the autosomal background. Here we study the genetics and evolution of Nup160-mediated hybrid lethality in three ways. First, we test for variability in Nup160-mediated hybrid lethality within and among the three species of the D. simulans clade- D. simulans, D. sechellia, and D. mauritiana. We show that the hybrid lethality of Nup160 is fixed in D. simulans and D. sechellia but absent in D. mauritiana. Second, we explore how the hybrid lethality of Nup160 depends on other loci in the autosomal background. We find that D. simulans Nup160-mediated hybrid lethality does not depend on the presence of D. melanogaster Nup96, and we find that D. simulans and D. mauritiana are functionally differentiated at Nup160 as well as at other autosomal factor(s). Finally, we use population genetics data to show that Nup160 has experienced histories of recurrent positive selection both before and after the split of the three D. simulans clade species ∼240,000 years ago. Our genetic results suggest that a hybrid lethal Nup160 allele evolved before the split of the three D. simulans clade species, whereas the other autosomal factor(s) evolved more recently.

Quantitative integration of genetic factors in the learning and production of canary song

Learned bird song is influenced by inherited predispositions. The canary is a model system for the interaction of genes and learning on behaviour, especially because some strains have undergone artificial selection for song. In this study, roller canaries (bred for low-pitched songs) and border canaries (whose song is higher pitched, similar to the wild-type) were interbred and backcrossed to produce 58 males that sorted into seven genetically distinct groups. All males were tutored with the same set of songs, which included both low- and high-pitched syllables. Individuals were consistent within genetic groups but differed between groups in the proportion of low- versus high-pitched syllables they learned and sang. Both sex-linked and autosomal factors affected song learning and song production, in an additive manner. Dominant Z-chromosome factors facilitated high-pitched syllable learning and production, whereas the sex-linked alleles associated with the switch to low-pitched syllables under artificial selection were largely recessive. With respect to autosomal effects, the most surprising result is that males in the same genetic group had almost identical repertoires. This result challenges two common preconceptions: that genetic changes at different loci lead to distinct phenotypic changes, and that genetic predispositions affect learning in simple and general ways. Rather, different combinations of genetic changes can be associated with the same phenotypic effect; and predispositions can be remarkably specific, such as a tendency to learn and sing one song element rather than another.

A selfish gene chastened: Tribolium castaneum Medea M 4 is silenced by a complementary gene

Maternal-effect dominant embryonic arrest (Medea) of Tribolium castaneum are autosomal factors that act maternally to cause the death of any progeny that do not inherit them. This selfish behavior is thought to result from a maternally expressed poison and zygotically expressed antidote. Medea factors and the hybrid incompatibility factor, H, have a negative interaction consistent with complementary genes of the Dobzhansky-Muller model for post-zygotic isolation. This negative interaction may result from H suppression of Medea zygotic antidote, leaving zygotes incompletely protected from maternal poison. I report here a test of the hypothesis that H also suppresses the Medea maternal poison. Viable F1 females were generated from a cross of Medea M4 strain males to H strain females. These females, heterozygous for both M4 and H, failed to express M4 maternal lethal activity when crossed to their male sibs. Transmission of non-M4 homologues from these females was confirmed using a dominant transgenic enhanced green fluorescent protein eye color marker, tightly linked in cis to M4. M4 beetles, lacking H, were selected from the F2 population. Female descendants of these clearly expressed M4 maternal lethal activity, indicating restoration of this activity after H was segregated away. I conclude that H, or a factor tightly linked to H, suppresses Medea M4 maternal poison.

A Novel Approach Identifying Hybrid Sterility QTL on the Autosomes of Drosophila simulans and D. mauritiana

When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW) sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could ‘mask’ the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56%) of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

Genetic differences and phenotypic plasticity in body size between high‐ and low‐altitude populations of the ground beetle Carabus tosanus

The body size of a univoltine carabid beetle Carabus tosanus on Shikoku Island, Japan, was clearly smaller in higher-altitude populations (subspecies), which possibly represents incipient speciation. To explore the determinants of altitudinal differences in body size in this species, we studied the degree of phenotypic plasticity by conducting rearing experiments at two constant temperatures and examined genetic differences through interpopulation crosses. At 15°C, C.tosanus had a longer developmental period and a shorter adult body than at 20°C. Nevertheless, variation in body size due to temperature effects (phenotypic plasticity) was small compared to the interpopulation differences, which suggests substantial genetic differences between populations (subspecies) at different altitudes. In F(1) offspring from crosses between a low-altitude (subspecies tosanus) and a high-altitude population (subspecies ishizuchianus), adult body length was affected by the genotypes of both parents, with an interaction effect of parental genotype and offspring sex. Further analyses revealed that adult body length was affected by sex-linked factors in addition to autosomal factors. These genetic differences in body size may have resulted from adaptations to different altitudes and may be important for the process of incipient speciation because body size differences could contribute to premating reproductive isolation.

Are acquired cystic kidney disease and autosomal dominant polycystic kidney disease risk factors for renal cell carcinoma in kidney transplant patients?

The potent immunosuppressive agents predispose the kidney transplant patients to the development of several malignancies. Primary renal cell carcinoma (RCC) accounts 4.6% of all cancers among kidney transplant recipients, 90% in native kidneys and 10% in the allograft (1). Only 45 cases of allograft RCC have been reported by the Cincinnati Transplant Tumor Registry (2). Apart from a few isolated case reports, there have been only three largest case series including 3 of 1250, 5 of 1073 and 8 of 2050 RTRs had RCC (3-5). Between 1984 and 2008, we diagnosed five RCC among 5532 kidney transplants (6). Lee et al. (7) showed that the prevalence of patients with RCC after renal transplantation was 0.8%. In a study by Cheung et al. (8), the prevalence of native kidney RCC after renal transplantation was 1.3%. Several risk factors have been associated with RCC in kidney transplant patients include increasing age, male gender, previous exposure to carcinogens, genetic predisposition, acquired cystic kidney disease (ACKD) and older age of donor (1,9). Older age and male gender were risk factors for development of RCC in our patients.(6) Lee et al. (7) examined acquired cystic kidney disease (ACKD) development as a risk factor of RCC in the both groups. It is of interest of that ACKD was more likely to be occurred in the dialysis patients than the kidney transplant recipient. In addition ACKD occurrence was strongly correlated to the development of RCC in dialysis patients when compared to the kidney transplant recipient (7). This finding means that the incidence of ACKD seems to be lower in kidney transplant patients than in dialysis individuals. Schwarz et al. (9) reported a relatively high prevalence of RCC in kidney transplant patients with ACKD. Therefore, they concluded that ACKD was a risk factor for RCC among kidney transplant recipients and screening such as ultrasound should be performed for RCC in such patients, which consistent with study of Heinz-Peer et al. (10) reported a high prevalence of RCC in patients undergoing kidney transplantation. In addition, Cheung et al. (8) showed a high prevalence of RCC in kidney transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) (8), although the association of ADPKD with RCC is very rare (11). Therefore, they concluded that ADPKD was a risk factor for RCC among kidney transplant recipients and screening such as ultrasound should be performed for RCC in such patients (8), which consistent with study of Hajj et al. (12).They reported a high prevalence of RCC in patients with end stage kidney disease as well as patients undergoing kidney transplantation(12). However, the increased development of RCC associated with ADPKD compared to the general population is controversial (13,14). In our previous study, 5 of 5532 kidney transplants had RCC; none of them had ADPKD (6). Moreover, in a large retrospective study, we enrolled 164 of 3725 transplant patients had history of ADPKD, 73% male and 23% female (unpublished data). None of them had RCC, but post-transplant diabetes mellitus was occurred in 16.7% of all patients. One, five and ten renal allograft survivals were 87.0%, 78.4% and 70.6%, respectively. We concluded that graft outcome after short- and long-term follow-up was promising and ADPKD was not a risk factor for development of the post-transplant malignancy. Although, relation between kidney cystic disease and RCC after kidney transplantation is still a controversial subject and further studies are require to provide a better understanding of this important clinical issue, we recommend a strict follow-up with annually ultrasonography in a such patients. Prompt and early diagnosis is the obvious cornerstone for successful management of these patients.

Behaviour genetic analysis of selective song learning in three inbred canary strains

Thirty-three male canaries were reared as isolates in acoustic chambers. Each male's sexchromosomes and autosomal background were known to strain. The research included two experiments. One tested the hypothesis that the low-pitched songs of waterslager canaries is due to a partial hearing deficit in the high frequency range of their hearing, limiting learning high-pitched syllables. That hypothesis was falsified and the apparent cause for the low-pitched songs was uncovered in the second experiment. That experiment tutored the males with a tutor tape that offered six different canary songs to learn from. The experimental subjects included roller, waterslager, and border canaries, their hybrids and backcrosses. The selective learning of each genetically different group was closely associated with their specific genetic background, and the results revealed that roller and waterslager canaries have very different genetic mechanisms affecting their song learning, and that a waterslager, recessive, autosomal factor, when homozygous, was associated with that strain's low-pitched songs. On the other hand, the low-pitched songs of roller canaries were primarily affected by a recessive sex-linked factor. Border canary selective learning was biased toward learning the higher-pitched syllables and tours characteristic of the songs of border and other type canary strains.

Dosage Regulation of the Active X Chromosome in Human Triploid Cells

In mammals, dosage compensation is achieved by doubling expression of X-linked genes in both sexes, together with X inactivation in females. Up-regulation of the active X chromosome may be controlled by DNA sequence–based and/or epigenetic mechanisms that double the X output potentially in response to autosomal factor(s). To determine whether X expression is adjusted depending on ploidy, we used expression arrays to compare X-linked and autosomal gene expression in human triploid cells. While the average X:autosome expression ratio was about 1 in normal diploid cells, this ratio was lower (0.81–0.84) in triploid cells with one active X and higher (1.32–1.4) in triploid cells with two active X's. Thus, overall X-linked gene expression in triploid cells does not strictly respond to an autosomal factor, nor is it adjusted to achieve a perfect balance. The unbalanced X:autosome expression ratios that we observed could contribute to the abnormal phenotypes associated with triploidy. Absolute autosomal expression levels per gene copy were similar in triploid versus diploid cells, indicating no apparent global effect on autosomal expression. In triploid cells with two active X's our data support a basic doubling of X-linked gene expression. However, in triploid cells with a single active X, X-linked gene expression is adjusted upward presumably by an epigenetic mechanism that senses the ratio between the number of active X chromosomes and autosomal sets. Such a mechanism may act on a subset of genes whose expression dosage in relation to autosomal expression may be critical. Indeed, we found that there was a range of individual X-linked gene expression in relation to ploidy and that a small subset (∼7%) of genes had expression levels apparently proportional to the number of autosomal sets.

Time‐shifted reproductive behaviours among fall armyworm (Noctuidae: Spodoptera frugiperda) host strains: evidence for differing modes of inheritance

The noctuid moth Spodoptera frugiperda consists of two strains associated with different larval host plants (most notably corn and rice). These strains exhibit differential temporal patterns of female calling and copulation during scotophase, with the corn strain more active earlier in the night. We investigated strain-specific constraints in reproductive timing, mating interactions between the two strains, and the mode of inheritance of timing of female calling, male calling, copulation and oviposition. We observed an allochronic shift of all reproductive behaviours by approximately 3 h and a parallel shift of nonreproductive locomotor activity, suggesting involvement of the circadian clock. The corn strain was more variable in the timing of calling and copulation than the rice strain. Rice strain females were more restricted in the timing of copulation than rice strain males, while such differences between the sexes were not apparent in the corn strain. There were significant interactions between the strains affecting onset times of copulation and male calling. The four investigated reproductive traits differed in their modes of inheritance: timing of female and male calling exhibited strong maternal effects, timing of copulation was controlled by a combination of maternal effects and corn strain dominant autosomal factors, and timing of oviposition was inherited in a corn strain dominant fashion. We conclude that the allochronic separation of reproduction between fall armyworm strains is asymmetric, less pronounced than previously thought, and under complex genetic control.

Are autosomal sex-determining factors of the housefly (Musca domestica) spreading north?

Multiple sex-determining factors have been found in natural populations of the housefly, Musca domestica. Their distribution seems to follow a geographical cline. The 'standard' system, with a male-determining factor, M, located on the Y chromosome, prevails at higher latitudes and altitudes. At lower latitudes and altitudes M factors have also been found on any of the five autosomes. Such populations often also harbour a dominant autosomal factor, FD, which induces female development even in the presence of several M factors. Autosomal M factors were first observed some 50 years ago. It has been hypothesized that following their initial appearance, they are spreading northwards, replacing the standard XY system, but this has never been systematically investigated. To scrutinize this hypothesis, we here compare the current distribution of autosomal M factors in continental Europe, on a transect running from Germany to southern Italy, with the distribution reported 25 years ago. Additionally, we analysed the frequencies of the FD factor, which has not been done before for European populations. In contrast to earlier predictions, we do not find a clear change in the distribution of sex-determining factors: as 25 years ago, only the standard XY system is present in the north, while autosomal M factors and the FD factor are prevalent in Italy. We discuss possible causes for this apparently stable polymorphism.

The genetics of hybrid male sterility between the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana: dominant sterility alleles in collinear autosomal regions.

F(1) hybrid male sterility is thought to result from interactions between loci on the X chromosome and dominant-acting loci on the autosomes. While X-linked loci that contribute to hybrid male sterility have been precisely localized in many animal taxa, their dominant autosomal interactors have been more difficult to localize precisely and/or have been shown to be of relatively smaller effect. Here, we identified and mapped at least four dominant autosomal factors contributing to hybrid male sterility in the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana. Using these results, we tested predictions of reduced recombination models of speciation. Consistent with these models, three of the four QTL associated with hybrid male sterility occur in collinear (uninverted) regions of these genomes. Furthermore, these QTL do not contribute significantly to hybrid male sterility in crosses between the sympatric species D. persimilis and D. pseudoobscura pseudoobscura. The autosomal loci identified in this study provide the basis for introgression mapping and, ultimately, for molecular cloning of interacting genes that contribute to F(1) hybrid sterility.

GR/GR deletions within the azoospermia factor c region on the Y chromosome might not be associated with spermatogenic failure

No statistically significant difference in deletion frequency was found between infertile patients and a control group. It is suggested that in some populations the gr/gr deletion might be an inconsequential polymorphism.

Study of the genetics of female sex pheromone production and male behavioral response in a moth, Ostrinia orientalis

AbstractInheritance patterns of female sex pheromone production and male behavioral response were studied in Ostrinia orientalis. Results showed that the production of the female sex pheromone in O. orientalis was mainly controlled by a single autosomal factor, while the male behavioral response was controlled by a sex‐linked major gene.

606. Molecular Characterization of Hereditary Factor VII Deficiency in Beagles

Hereditary factor VII deficiency is the most common autosomal recessive inherited factor deficiency. Several mutations in the coding sequence of the human factor VII (hFVII) gene have been characterized and clinically associated with bleeding tendencies of variable severity.

FEMALE STERILITY IN HYBRIDS BETWEEN ANOPHELES GAMBIAE AND A. ARABIENSIS, AND THE CAUSES OF HALDANE'S RULE

Although F1 female hybrids between Anopheles gambiae and A. arabiensis are fully fertile, sterility is present in backcross females. Here we report the results of a study into the genetic basis of backcross female sterility. Using 23 markers, we performed quantitative trait loci (QTL) mapping analyses to identify chromosomal regions involved in hybrid female sterility. We found that female sterility in backcrosses in both directions is primarily caused by interspecific interactions between a heterozygous X chromosome and recessive autosomal factors. In addition, our data provide support for two theories implicated in Haldane's rule in a single taxon. A comparison with data from a previous study shows that male hybrid sterility QTL are present in higher numbers than female hybrid sterility QTL. Furthermore, autosomal female sterility factors tend to be recessive, supporting the dominance theory for female sterility. Finally, our data indicate a very large effect of the X chromosome from both species on hybrid female sterility, despite the fact that the X chromosome represents less than 9% of the genome. However, this could be the result of a lack of introgression of the X chromosome between A. gambiae and A. arabiensis, rather than a faster evolution of sterility factors on the X chromosome.