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

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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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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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

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400853 ◽

2019 ◽

Vol 10 (2) ◽

pp. 525-537 ◽

Cited By ~ 4

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

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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Loss of maternal ANNEXIN A10 via a 34-kb deleted-type copy number variation is associated with embryonic mortality in Japanese Black cattle

BMC Genomics ◽

10.1186/s12864-016-3312-z ◽

2016 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Shinji Sasaki ◽

Takayuki Ibi ◽

Takayuki Akiyama ◽

Moriyuki Fukushima ◽

Yoshikazu Sugimoto

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Embryonic Mortality ◽

Japanese Black Cattle ◽

Annexin A10 ◽

Number Variation

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Genome-wide identification of copy number variation using high-density single-nucleotide polymorphism array in Japanese Black cattle

BMC Genetics ◽

10.1186/s12863-016-0335-z ◽

2016 ◽

Vol 17 (1) ◽

Cited By ~ 16

Author(s):

Shinji Sasaki ◽

Toshio Watanabe ◽

Shota Nishimura ◽

Yoshikazu Sugimoto

Keyword(s):

Single Nucleotide Polymorphism ◽

Copy Number Variation ◽

Copy Number ◽

Single Nucleotide Polymorphism Array ◽

High Density ◽

Nucleotide Polymorphism ◽

Japanese Black Cattle ◽

Single Nucleotide ◽

Genome Wide ◽

Number Variation

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Human gene copy number variation and infectious disease

Human Genetics ◽

10.1007/s00439-014-1457-x ◽

2014 ◽

Vol 133 (10) ◽

pp. 1217-1233 ◽

Cited By ~ 54

Author(s):

Edward J. Hollox ◽

Boon-Peng Hoh

Keyword(s):

Infectious Disease ◽

Copy Number Variation ◽

Copy Number ◽

Human Gene ◽

Gene Copy Number ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation

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Case Report: Neuroblastoma Breakpoint Family Genes Associate With 1q21 Copy Number Variation Disorders

Frontiers in Genetics ◽

10.3389/fgene.2021.728816 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lijuan Zhu ◽

Xiaoji Su

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Genomic Sequence ◽

Clinical Phenotype ◽

Clinical Manifestations ◽

Wild Type ◽

Craniofacial Dysmorphism ◽

Number Variation ◽

Pathogenic Gene ◽

Chromosome 1Q21

Microduplications and reciprocal microdeletions of chromosome 1q21. 1 and/or 1q21.2 have been linked to variable clinical features, but the underlying pathogenic gene(s) remain unclear. Here we report that distinct microduplications were detected on chromosome 1q21.2 (GRCh37/hg19) in a mother (255 kb in size) and her newborn daughter (443 kb in size), while the same paternal locus was wild-type. Although the two microduplications largely overlap in genomic sequence (183 kb overlapping), the mother showed no clinical phenotype while the daughter presented with several features that are commonly observed on 1q21 microduplication or microdeletion patients, including developmental delay, craniofacial dysmorphism, congenital heart disease and sensorineural hearing loss. NBPF15 and NBPF16, two involved genes that are exclusively duplicated in the proband, may be the cause of the clinical manifestations. This study supports an association between NBPF genes and 1q21 copy number variation disorders.

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