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Abstract Chromosomal inversions have long been appreciated as an important source of genetic diversity, local adaptation, and speciation. However, selection pressures maintaining ancestral and derived alleles at high frequency over extended periods of time remain poorly characterized. Using genome-wide single-nucleotide polymorphism markers and shared barcodes of linked-read sequences from 20 wild and 7 captive zebra finches Taeniopygia guttata, we systematically scanned a high-quality zebra finch reference genome and identified all large polymorphic inversions that segregate at high minor allele frequencies. Apart from the known polymorphic inversions on chromosomes Tgu5, Tug11, Tgu13, and TguZ, we characterized two inversions on microchromosomes Tgu26 and Tgu27 and identified another eight putative inversions, located mostly on microchromosomes and ranging in size from 0.42 to 65.22 Mb. Population genomic analyses show that most of the six bona fide inversions are complex, containing short nested inversions. The early inversions emerged an estimated 0.6 to 2.2 million years ago and segregate at relatively high frequencies in the wild (minor haplotype frequency range: 0.289 to 0.429). Based on fitness-related measures of about 5,000 captive zebra finches, we conclude that three of the inversion polymorphisms (Tgu11, Tgu27, and TguZ) may be maintained by net heterosis. In the youngest of the six inversions (Tgu13), the derived haplotype showed weak positive additive effects on various fitness components. In combination with previous discoveries, we provide a comprehensive overview of the genomic distribution and evolutionary dynamics of large polymorphic inversions in the panmictic zebra finch. Our findings highlight (i) that microchromosomes may harbor quite a few additional inversion polymorphisms, (ii) that most of the inversions contain smaller nested or overlapping inversions, and (iii) that inversions were most likely maintained by weak heterosis with small fitness effects requiring large sample sizes to be detected.

Background Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. Results We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis -acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. Conclusions We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.

The telomere-to-telomere (T2T) complete human reference has significantly improved our ability to characterize genome structural variation. To understand its impact on inversion polymorphisms, we remapped data from 41 genomes against the T2T reference genome and compared it to the GRCh38 reference. We find a ~ 21% increase in sensitivity improving mapping of 63 inversions on the T2T reference. We identify 26 misorientations within GRCh38 and show that the T2T reference is three times more likely to represent the correct orientation of the major human allele. Analysis of 10 additional samples reveals novel rare inversions at chromosomes 15q25.2, 16p11.2, 16q22.1–23.1, and 22q11.21.

How genetic variance for fitness is maintained is incompletely understood. Mutation-selection balance and single-locus overdominance cannot account for the large variance observed. Recent work suggests that antagonistic balancing selection, favoring different alleles in different contexts and involving beneficial dominance reversals, might contribute to maintaining fitness variance. However, while this mechanism is plausible, evidence for dominance reversals remains scarce. Here, we study how In(3R)Payne, a balanced inversion polymorphism in Drosophila melanogaster, affects gene expression and chromatin accessibility by using RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing). We find that, in embryos, the inverted (INV) arrangement tends to have dominant effects, while the standard (STD) arrangement behaves like a recessive Mendelian allele. Yet, in wing discs, this pattern is reversed: STD has mostly dominant effects, whereas INV behaves recessively. Since this shift in the dominance of the INV “allele” between developmental contexts affects the expression of suites of genes in a concerted manner, it might be mediated by a dominance modifier, for example, a transcription factor. In favor of this idea, 25% of the differentially expressed genes between INV and STD encode transcription factors. Interestingly, while only four differentially expressed genes are shared between embryos and wing discs, one of them is HP1c, a chromatin-binding protein and major transcriptional regulator, and thus a promising candidate for mediating the context-dependent change in dominance. Although the relationship between these patterns and fitness is presently unknown, our observations are consistent with a potential role of reversals (or, more generally, shifts) of dominance in maintaining inversion polymorphism.

Clines in chromosomal inversion polymorphisms—presumably driven by climatic gradients—are common but there is surprisingly little evidence for selection acting on them. Here we address this long-standing issue in Drosophila melanogaster by using diagnostic single nucleotide polymorphism (SNP) markers to estimate inversion frequencies from 28 whole-genome Pool-seq samples collected from 10 populations along the North American east coast. Inversions In(3L)P, In(3R)Mo, and In(3R)Payne showed clear latitudinal clines, and for In(2L)t, In(2R)NS, and In(3R)Payne the steepness of the clinal slopes changed between summer and fall. Consistent with an effect of seasonality on inversion frequencies, we detected small but stable seasonal fluctuations of In(2R)NS and In(3R)Payne in a temperate Pennsylvanian population over 4 years. In support of spatially varying selection, we observed that the cline in In(3R)Payne has remained stable for >40 years and that the frequencies of In(2L)t and In(3R)Payne are strongly correlated with climatic factors that vary latitudinally, independent of population structure. To test whether these patterns are adaptive, we compared the amount of genetic differentiation of inversions versus neutral SNPs and found that the clines in In(2L)t and In(3R)Payne are maintained nonneutrally and independent of admixture. We also identified numerous clinal inversion-associated SNPs, many of which exhibit parallel differentiation along the Australian cline and reside in genes known to affect fitness-related traits. Together, our results provide strong evidence that inversion clines are maintained by spatially—and perhaps also temporally—varying selection. We interpret our data in light of current hypotheses about how inversions are established and maintained.

Allozyme loci are frequently found non randomly associated to the chromosomal inversions in which they are included in Drosophila. Two opposite views compete to explain strong allozyme‐by‐inversion gametic disequilibria: they result from natural selection or, conversely, merely represent remnants of associations accidentally established at the origin of inversions. Empirical efforts aimed at deciding between adaptive and historical scenarios have focused on the spatial distribution of disequilibria. Yet, the evolutionary significance of these associations remains uncertain. I report here the results of a time‐series analysis of the seasonal variation of alleles at six allozyme loci (Acph, Lap, Pept‐1, Ao, Mpi, and Xdh) in connection with the O chromosomal polymorphisms of D. subobscura. The findings were: (1) in the segment I of the O chromosome, Lap and Pept‐1 allozymes changed seasonally in a cyclical fashion within the ST gene arrangement, but they changed erratically within the 3+4 gene configuration; (2) the frequencies of Lap111 and Pept‐10,40 within ST dropped to their lowest values in early and late summer, respectively, when the seasonal level of the ST arrangement is lowest. Furthermore, Lap1,11 and Pept‐10,40 covary with ST only within these seasons, yet in a fashion inconsistent with these alleles having a major influence on the dynamics of the inversion; (3) seasonal cycling of alleles within inversions were not detected at Acph, Ao, Mpi, and Xdh, yet these loci are nearly monomorphic at the study population, and/or their sampled series were shorter than those for Lap and Pept‐1; and (4) simply monitoring allozyme frequencies separately for each inversion proved to be superior, for evidencing the seasonal cycles of the disequilibria, to the use of the D' coefficient of association. Observed seasonal cycles of allozymes within inversions likely reflect natural selection.

There is a growing appreciation that chromosome inversions affect rates of adaptation, speciation, and the evolution of sex chromosomes. Comparative genomic studies have identified many new paracentric inversion polymorphisms. Population models suggest that inversions can spread by reducing recombination between alleles that independently increase fitness, without epistasis or coadaptation. Areas of linkage disequilibrium extend across large inversions but may be interspersed by areas with little disequilibrium. Genes located within inversions are associated with a variety of traits including those involved in climatic adaptation. Inversion polymorphisms may contribute to speciation by generating underdominance owing to inviable gametes, but an alternative view gaining support is that inversions facilitate speciation by reducing recombination, protecting genomic regions from introgression. Likewise, inversions may facilitate the evolution of sex chromosomes by reducing recombination between sex determining alleles and alleles with sex-specific effects. However, few genes within inversions responsible for fitness effects or speciation have been identified.

Background Inversion polymorphisms constitute an evolutionary puzzle: they should increase embryo mortality in heterokaryotypic individuals but still they are widespread in some taxa. Some insect species have evolved mechanisms to reduce the cost of embryo mortality but humans have not. In birds, a detailed analysis is missing although intraspecific inversion polymorphisms are regarded as common. In Australian zebra finches ( Taeniopygia guttata ), two polymorphic inversions are known cytogenetically and we set out to detect these two and potentially additional inversions using genomic tools and study their effects on embryo mortality and other fitness-related and morphological traits. Results Using whole-genome SNP data, we screened 948 wild zebra finches for polymorphic inversions and describe four large (12–63 Mb) intraspecific inversion polymorphisms with allele frequencies close to 50 %. Using additional data from 5229 birds and 9764 eggs from wild and three captive zebra finch populations, we show that only the largest inversions increase embryo mortality in heterokaryotypic males, with surprisingly small effect sizes. We test for a heterozygote advantage on other fitness components but find no evidence for heterosis for any of the inversions. Yet, we find strong additive effects on several morphological traits. Conclusions The mechanism that has carried the derived inversion haplotypes to such high allele frequencies remains elusive. It appears that selection has effectively minimized the costs associated with inversions in zebra finches. The highly skewed distribution of recombination events towards the chromosome ends in zebra finches and other estrildid species may function to minimize crossovers in the inverted regions.

Chromosomal inversions allow genetic divergence of locally adapted populations by reducing recombination between chromosomes with different arrangements. Divergence between populations (or hybridization between species) is expected to leave signatures in the neutral genetic diversity of the inverted region. Quantitative expectations for these patterns, however, have not been obtained. Here, we develop coalescent models of neutral sites linked to an inversion polymorphism in two locally adapted populations. We consider two scenarios of local adaptation: selection on the inversion breakpoints and selection on alleles inside the inversion. We find that ancient inversion polymorphisms cause genetic diversity to depart dramatically from neutral expectations. Other situations, however, lead to patterns that may be difficult to detect; important determinants are the age of the inversion and the rate of gene flux between arrangements. We also study inversions under genetic drift, finding that they produce patterns similar to locally adapted inversions of intermediate age. Our results are consistent with empirical observations, and provide the foundation for quantitative analyses of the roles that inversions have played in speciation.

The adaptive value of chromosomal inversions continues raising relevant questions in evolutionary biology. In many species of the Drosophila genus, different inversions have been recognized to be related to thermal adaptation, but it is necessary to determine to which specific climatic variables the inversions are adaptive. With this aim, the behavior of thermal adapted inversions of Drosophila subobscura regarding climatic variables was studied in the natural population of Avala (Serbia) during the 2014–2017 period. The results obtained were compared with those previously reported in the Font Groga (Barcelona, Spain) population, which presents different climatic and environmental conditions. In both populations, it was observed that most thermal adapted inversions were significantly associated with the first, second or both principal components, which were related with maximum, minimum and mean temperatures. Moreover, a significant increase over years (2004–2017) for the minimum temperature was detected. In parallel, a significant variation over time in Avala was only observed for the frequencies of ‘warm’ and ‘non-thermal’ adapted inversions of the U chromosome. However, stability in the chromosomal inversion polymorphism was observed for the 2014–2017 period which might result from the temporal span of the study and/or selective process acting on the population.