A macromutation eliminates colour patterning in captive butterflies

Captive populations often harbor variation that is not present in the wild due to artificial selection. Recent efforts to map this variation have provided insights into the genetic and molecular basis of variation. Heliconius butterflies display a large array of pattern variants in the wild and the genetic basis of these patterns has been well-described. Here we sought to identify the genetic basis of an unusual pattern variant that is instead found in captivity, the ivory mutant, in which all scales on both the wings and body become white or yellow. Using a combination of autozygosity mapping and coverage analysis from 37 captive individuals, we identify a 78kb deletion at the cortex wing patterning locus as the ivory mutation. This deletion is undetected among 458 wild Heliconius genomes samples, and its dosage explains both homozygous and heterozygous ivory phenotypes found in captivity. The deletion spans a large 5' region of the cortex gene that includes a facultative 5' UTR exon detected in larval wing disk transcriptomes. CRISPR mutagenesis of this exon replicates the wing phenotypes from coding knock-outs of cortex, consistent with a functional role of ivory-deleted elements in establishing scale color fate. Population demographics reveal that the stock giving rise to the ivory mutant has a mixed origin from across the wild range of H. melpomene, and supports a scenario where the ivory mutation occurred after the introduction of cortex haplotypes from Ecuador. Homozygotes for the ivory deletion are inviable, joining 40 other examples of allelic variants that provide heterozygous advantage in animal populations under artificial selection by fanciers and breeders. Finally, our results highlight the promise of autozygosity and association mapping for identifying the genetic basis of aberrant mutations in captive insect populations.

Autozygosity mapping in consanguineous Pakistani families identifies nine non-overlapping novel linkage intervals for autosomal recessive non-syndromic mental retardation (AR-NSMR); shows genetic heterogeneity for AR-NSMR

Psychological disturbance (PD) or cerebral dysfunction (CD) occupying several clinical areas having defining features of mental retardation. Currently we have designed to investigate heritable heterogeneity in Pakistani consanguineous couples with recessive autosomal intellectual abnormilaties. Department of Biotechnology UST-Bannu and WJC Panum institute University of Copenhagen Denmark from January 2017 to March 2019. Cohort of Three consanguineous families with multiple birth defects was selected from different regions of Pakistan for molecular analysis analysis. All affected individuals in the cohort showed mental disturbances. Deoxyribonucleic acid (DNA) was extracted and subjected to STS (Single tagged sequence) marker analyses to all known non syndromic autosomal recessive mental retardation (NS-ARMR) genes while autozygosity mapping was performed by advanced SNP techniques. STS (Single tagged sequence) marker analyses showed exclusion to all known non syndromic autosomal recessive mental retardation (NS-ARMR) genes. Autozygosity mapping have shown novel nine linkage intervals. Continuous...

Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between −0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ≃45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ≃2–5% (P-value< 2.3 × 10−6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value= 2.0 × 10−6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.

Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25,000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between −0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized parameters led to a ≃45% increase in the correlation between parental genetic relatedness and offspring ROH compared to using predefined parameters. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, using autozygosity mapping for common and rare autozygous segments, we identified three maternal loci in TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ≃2-5% (p-value< 2.3×10−6). We also found suggestive evidence of a fetal locus at 3q22.2, in the RYK gene region (p-value= 6.5×10−6). Autozygosity mapping may provide new insights on the genetic determinants and architecture of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.Author summaryMating between relatives has an effect on offspring’s health and fitness in a number of species. In the offspring of genetically related parents, this is translated into long segments of the genome in the homozygous form (the same copy is inherited from each parent), but there is no consensus on how long these segments must be. In this study, we used dense genetic data from parent-offspring trios to optimize the detection of long segments of the genome. Our optimized long homozygous segments increased the correlation between parental genetic relatedness and offspring runs of homozygosity by ≃45% compared to widely used parameters. Furthermore, while preterm delivery is the global leading cause of mortality in children under 5 years, the degree to which long homozygous segments affect human delivery timing is unknown. We observed no maternal, paternal nor fetal effects of the proportion of the genome covered by homozygous segments on time-to-spontaneous delivery. However, by mapping these segments to the genome, we found evidence supporting three specific maternal segments falling on TBC1D1, SIGLECs and EDN2 gene regions to be associated with lower time-to-spontaneous onset of delivery. Future studies should assess the functional impact of these genes on spontaneous onset of delivery.

Advances in identification of genes involved in autosomal recessive intellectual disability: a brief review

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1%–3% of the general population. The number of ID-causing genes is high. Many X-linked genes have been implicated in ID. Autosomal dominant genes have recently been the focus of several large-scale studies. The total number of autosomal recessive ID (ARID) genes is estimated to be very high, and most are still unknown. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause ARID has lagged behind, predominantly due to non-availability of sizeable families. A commonly used approach to identify genetic loci for recessive disorders in consanguineous families is autozygosity mapping and whole-exome sequencing. Combination of these two approaches has recently led to identification of many genes involved in ID. These genes have diverse function and control various biological processes. In this review, we will present an update regarding genes that have been recently implicated in ID with focus on ARID.