Synaptonemal Complex-Deficient Drosophila melanogaster Females Exhibit Rare DSB Repair Events, Recurrent Copy-Number Variation, and an Increased Rate of de Novo Transposable Element Movement

Genetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. DSBs can also be made by other mechanisms, such as the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy-number changes, translocations, and/or aneuploid gametes. In Drosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs in D. melanogaster mutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy-number variation still occurs and meiotic DSB repair by gene conversion occurs infrequently. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why the sequence, but not structure, of SC proteins is rapidly evolving.

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Synaptonemal complex-deficient Drosophila melanogaster females exhibit rare DSB repair events, recurrent copy number variation, and an increased rate of de novo transposable element movement

10.1101/814186 ◽

2019 ◽

Author(s):

Danny E. Miller

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Transposable Element ◽

Synaptonemal Complex ◽

Copy Number ◽

De Novo ◽

Wild Type ◽

Dsb Repair ◽

Number Variation ◽

Element Movement

ABSTRACTGenetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. Additionally, DSBs are made by the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy number variations, translocations, and/or aneuploid gametes. In Drosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs in D. melanogaster mutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy number variation still occurs but meiotic DSB repair by gene conversion may occur only rarely. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why SC proteins are among the most rapidly evolving in any organism.

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De Novo Chromosome Copy Number Variation in Fanconi Anemia-Associated Hematopoietic Defects

10.21236/ada586051 ◽

2013 ◽

Author(s):

Niall G. Howlett

Keyword(s):

Copy Number Variation ◽

Fanconi Anemia ◽

Copy Number ◽

De Novo ◽

Chromosome Copy Number ◽

Number Variation ◽

Chromosome Copy Number Variation

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A 44-kb deleted-type copy number variation is associated with decreasing complement component activity and calf mortality in Japanese Black cattle

BMC Genomics ◽

10.1186/s12864-021-07415-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Shinji Sasaki ◽

Youko Miki ◽

Takayuki Ibi ◽

Hiroyuki Wakaguri ◽

Yuichi Yoshida ◽

...

Keyword(s):

Infectious Disease ◽

Copy Number Variation ◽

Copy Number ◽

Risk Allele ◽

Wild Type ◽

Japanese Black Cattle ◽

Complement Activity ◽

Categorical Trait ◽

Number Variation ◽

Calf Mortality

Abstract Background Calf mortality generally occurs in calves prior to weaning, which is a serious problem in cattle breeding. Several causative variants of monogenic Mendelian disorders in calf mortality have been identified, whereas genetic factors affecting the susceptibility of calves to death are not well known. To identify variants associated with calf mortality in Japanese Black cattle, we evaluated calf mortality as a categorical trait with a threshold model and performed a genome-wide copy number variation (CNV) association study on calf mortality. Results We identified a 44-kb deleted-type CNV ranging from 103,317,687 to 103,361,802 bp on chromosome 5, which was associated with the mortality of 1–180-day-old calves. The CNV harbored C1RL, a pseudogene, and an IncRNA localized in the C1R and C1S gene cluster, which is a component of the classical complement activation pathway for immune complexes for infectious pathogens. The average complement activity in CNVR_221 homozygotes at postnatal day 7 was significantly lower than that of wild-type animals and heterozygotes. The frequency of the risk allele in dead calves suffering from diarrhea and pneumonia and in healthy cows was 0.35 and 0.28, respectively (odds ratio = 2.2, P = 0.016), suggesting that CNVR_221 was associated with the mortality of Japanese Black calves suffering from an infectious disease. Conclusions This study identified a deleted-type CNV associated with the mortality of 1–180-day-old calves. The complement activity in CNVR_221 homozygotes was significantly lower than that in heterozygotes and wild type animals. The frequency of the risk allele was higher in dead calves suffering from an infectious disease than in healthy cows. These results suggest that the existence of CNVR_221 in calves could be attributed to a reduction in complement activity, which in turn leads to susceptibility to infections. Thus, the risk allele could serve as a useful marker to reduce the mortality of infected Japanese Black calves.

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Insights into dispersed duplications and complex structural mutations from whole genome sequencing 706 families

10.1101/2020.08.03.235358 ◽

2020 ◽

Author(s):

Christopher W. Whelan ◽

Robert E. Handsaker ◽

Giulio Genovese ◽

Seva Kashin ◽

Monkol Lek ◽

...

Keyword(s):

Gene Expression ◽

Copy Number Variation ◽

Copy Number ◽

De Novo ◽

Whole Genome ◽

Sequencing Data ◽

Number Variation ◽

Structural Mutations ◽

Or Gene ◽

Genomic Locations

AbstractTwo intriguing forms of genome structural variation (SV) – dispersed duplications, and de novo rearrangements of complex, multi-allelic loci – have long escaped genomic analysis. We describe a new way to find and characterize such variation by utilizing identity-by-descent (IBD) relationships between siblings together with high-precision measurements of segmental copy number. Analyzing whole-genome sequence data from 706 families, we find hundreds of “IBD-discordant” (IBDD) CNVs: loci at which siblings’ CNV measurements and IBD states are mathematically inconsistent. We found that commonly-IBDD CNVs identify dispersed duplications; we mapped 95 of these common dispersed duplications to their true genomic locations through family-based linkage and population linkage disequilibrium (LD), and found several to be in strong LD with genome-wide association (GWAS) signals for common diseases or gene expression variation at their revealed genomic locations. Other CNVs that were IBDD in a single family appear to involve de novo mutations in complex and multi-allelic loci; we identified 26 de novo structural mutations that had not been previously detected in earlier analyses of the same families by diverse SV analysis methods. These included a de novo mutation of the amylase gene locus and multiple de novo mutations at chromosome 15q14. Combining these complex mutations with more-conventional CNVs, we estimate that segmental mutations larger than 1kb arise in about one per 22 human meioses. These methods are complementary to previous techniques in that they interrogate genomic regions that are home to segmental duplication, high CNV allele frequencies, and multi-allelic CNVs.Author SummaryCopy number variation is an important form of genetic variation in which individuals differ in the number of copies of segments of their genomes. Certain aspects of copy number variation have traditionally been difficult to study using short-read sequencing data. For example, standard analyses often cannot tell whether the duplicated copies of a segment are located near the original copy or are dispersed to other regions of the genome. Another aspect of copy number variation that has been difficult to study is the detection of mutations in the copy number of DNA segments passed down from parents to their children, particularly when the mutations affect genome segments which already display common copy number variation in the population. We develop an analytical approach to solving these problems when sequencing data is available for all members of families with at least two children. This method is based on determining the number of parental haplotypes the two siblings share at each location in their genome, and using that information to determine the possible inheritance patterns that might explain the copy numbers we observe in each family member. We show that dispersed duplications and mutations can be identified by looking for copy number variants that do not follow these expected inheritance patterns. We use this approach to determine the location of 95 common duplications which are dispersed to distant regions of the genome, and demonstrate that these duplications are linked to genetic variants that affect disease risk or gene expression levels. We also identify a set of copy number mutations not detected by previous analyses of sequencing data from a large cohort of families, and show that repetitive and complex regions of the genome undergo frequent mutations in copy number.

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Ribosomal DNA and Stellate gene copy number variation on the Y chromosome of Drosophila melanogaster.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.86.6.1944 ◽

1989 ◽

Vol 86 (6) ◽

pp. 1944-1948 ◽

Cited By ~ 51

Author(s):

E. M. Lyckegaard ◽

A. G. Clark

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Y Chromosome ◽

Ribosomal Dna ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation

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Analysis of copy-number variation, insertional polymorphism, and methylation status of the tiniest class I (TRIM) and class II (MITE) transposable element families in various rice strains

Plant Cell Reports ◽

10.1007/s00299-011-1209-5 ◽

2011 ◽

Vol 31 (5) ◽

pp. 885-893 ◽

Cited By ~ 10

Author(s):

Omer Baruch ◽

Khalil Kashkush

Keyword(s):

Copy Number Variation ◽

Transposable Element ◽

Copy Number ◽

Methylation Status ◽

Class Ii ◽

Class I ◽

Number Variation ◽

Insertional Polymorphism

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Rare De Novo Germline Copy-Number Variation in Testicular Cancer

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2012.06.019 ◽

2012 ◽

Vol 91 (2) ◽

pp. 379-383 ◽

Cited By ~ 12

Author(s):

Zsofia K. Stadler ◽

Diane Esposito ◽

Sohela Shah ◽

Joseph Vijai ◽

Boris Yamrom ◽

...

Keyword(s):

Copy Number Variation ◽

Testicular Cancer ◽

Copy Number ◽

De Novo ◽

Number Variation

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Impact of Gene Copy Number Variation on Anesthesia in Drosophila melanogaster

Anesthesiology ◽

10.1097/aln.0b013e3181a3276c ◽

2009 ◽

Vol 111 (1) ◽

pp. 15-24 ◽

Cited By ~ 4

Author(s):

Debasmita P. Alone ◽

Jason C. Rodriguez ◽

Cameron L. Noland ◽

Howard A. Nash

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation ◽

Righting Reflex ◽

The Difference ◽

Average Size

Background Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed, but effects on sensitivity to volatile anesthetics have not been assessed in any organism. Methods The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which was heterozygous for a deletion of average size 400 kb. Over 200 strains were examined, thereby scanning approximately half of the fly genome. Results Although the vast majority of deletion heterozygotes were indistinguishable from the control, eight had significantly altered sensitivity to halothane. Genetic tests supported the hypothesis that the change in anesthetic sensitivity was the result of reduction in copy number and not adventitious mutations in the strains. Among the eight outliers, the difference in halothane potency ranged from a 25% increase to a 15% decrease. Changes of similar magnitude but distinctive patterns were found when these lines were tested with enflurane, isoflurane, and sevoflurane. Conclusions Variation in gene copy number has a significant impact on anesthetic sensitivity in Drosophila melanogaster. The level of transcription of a few genes must thus be limiting for a normal response to volatiles. Coupling between gene copy and gene expression is universal, and the components of the fly's nervous system are highly conserved; therefore, this work provides a rationale for investigating the clinical impact of copy number variation.

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