Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

Xiangyu Yang; Yafei Mao; Xuan-Kai Wang; Dong-Ni Ma; Zhen Xu; Neng Gong; Barbara Henning; Xu Zhang; Guang He; Yong-Yong Shi; Evan E. Eichler; Zhi-Qiang Li; Eiki Takahashi; Wei-Dong Li

doi:10.24272/j.issn.2095-8137.2022.514

Volume 44 Issue 5

Sep. 2023

Turn off MathJax

Article Contents

Article Navigation > Zoological Research > 2023 > 44(5): 837-847

Xiangyu Yang, Yafei Mao, Xuan-Kai Wang, Dong-Ni Ma, Zhen Xu, Neng Gong, Barbara Henning, Xu Zhang, Guang He, Yong-Yong Shi, Evan E. Eichler, Zhi-Qiang Li, Eiki Takahashi, Wei-Dong Li. Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing. Zoological Research, 2023, 44(5): 837-847. doi: 10.24272/j.issn.2095-8137.2022.514

Citation:

Xiangyu Yang, Yafei Mao, Xuan-Kai Wang, Dong-Ni Ma, Zhen Xu, Neng Gong, Barbara Henning, Xu Zhang, Guang He, Yong-Yong Shi, Evan E. Eichler, Zhi-Qiang Li, Eiki Takahashi, Wei-Dong Li. Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing. Zoological Research, 2023, 44(5): 837-847. doi: 10.24272/j.issn.2095-8137.2022.514

Citation:

Xiangyu Yang, Yafei Mao, Xuan-Kai Wang, Dong-Ni Ma, Zhen Xu, Neng Gong, Barbara Henning, Xu Zhang, Guang He, Yong-Yong Shi, Evan E. Eichler, Zhi-Qiang Li, Eiki Takahashi, Wei-Dong Li. Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing. Zoological Research, 2023, 44(5): 837-847. doi: 10.24272/j.issn.2095-8137.2022.514

PDF( 4701 KB)

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

doi: 10.24272/j.issn.2095-8137.2022.514

Xiangyu Yang^{1, 2, 3},
Yafei Mao^{1, 5},
Xuan-Kai Wang¹,
Dong-Ni Ma^{1, 3},
Zhen Xu⁶,
Neng Gong⁶,
Barbara Henning⁵,
Xu Zhang^{1, 3},
Guang He¹,
Yong-Yong Shi^{1, 7},
Evan E. Eichler^{5, 8},
Zhi-Qiang Li^{1, 7
,
,},
Eiki Takahashi^{1, 9
,
,},
Wei-Dong Li^{1, 2, 3, 4
,
,}

1.
Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China
2.
Institute of Psychology and Behavioral Science, Shanghai Jiao Tong University, Shanghai 200030, China
3.
WLA Laboratories, World Laureates Association, Shanghai 201203, China
4.
Center for Brain Health and Brain Technology, Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai 200240, China
5.
Department of Genome Sciences, University of Washington School of Medicine, Seattle WA 98195, USA
6.
Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
7.
Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes, Qingdao University, Qingdao, Shandong 266003, China
8.
Howard Hughes Medical Institute, University of Washington, Seattle WA 98195, USA
9.
Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

The raw genomic sequencing reads can be downloaded from the NCBI (PRJNA807054), China National Center for Bioinformation (PRJCA016608), and Science Data Bank databases (DOI: 10.57760/sciencedb.08059).
Supplementary data to this article can be found online.
E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. All other authors declare no competing interests.
X.Y., Y.M., and W.D.L. designed the experiment. X.Y., Z.X., E.T., N.G., and W.D.L. contributed to sample collection and sample processing. X.Y., Y.M., X.K.W., Z.Q.L., B.H., G.H., and Y.Y.S. contributed to data analysis. D.N.M. and X.Z. contributed to SNP and CNV validation. E.E.E. provided computational resources. X.Y., Y.M., X.K.W., W.D.L., E.T., and Z.Q.L. generated tables and figures and drafted the manuscript. All authors contributed to editing and approved the final version of the manuscript.

Funds: This work was supported by the National Natural Science Foundation of China (82001372), National Key Research and Development Program of China (2018YFE0126700), Shanghai Jiao Tong University 2030 Initiative (WH510363001-7), Shanghai Municipal Commission of Science and Technology Program (21dz2210100), and Shanghai Education Commission Research and Innovation Program (2019-01-07-00-02-E00037), as well as a National Institutes of Health (NIH) grant (5R01HG002385) to E.E.E.

More Information

Corresponding author: E-mail: lizqsjtu@163.com; eiki.takahashi.sjt@gmail.com; liwd@sjtu.edu.cn
Received Date: 2023-04-23
Accepted Date: 2023-07-26

Published Online: 2023-07-27

Publish Date: 2023-09-18

Abstract

Abstract

The common marmoset (Callithrix jacchus) has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies. Epileptic marmosets have been independently reported in two Asian primate research centers. Nevertheless, the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated. Here, we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing. We identified 14 558 184 single nucleotide polymorphisms (SNPs) from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples. Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers. In addition, SNP and copy number variation (CNV) analyses suggested that the WW domain-containing oxidoreductase (WWOX) and Tyrosine-protein phosphatase nonreceptor type 21 (PTPN21) genes may be associated with epilepsy in marmosets. Notably, KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets. This study provides valuable population genomic resources for marmosets in two Asian primate centers. Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers, while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.
- Common marmoset (Callithrix jacchus),
- Population genetics,
- Whole-genome sequencing,
- Genetic chimerism,
- Epilepsy,
- Risk locus

FullText(HTML)

References(65)

References

[1]	Battaglia A, Guerrini R. 2005. Chromosomal disorders associated with epilepsy. Epileptic Disorders, 7(3): 181−192.
[2]	Benirschke K, Anderson JM, Brownhill LE. 1962. Marrow chimerism in marmosets. Science, 138(3539): 513−515. doi: 10.1126/science.138.3539.513
[3]	Breton VL, Aquilino MS, Repudi S, et al. 2021. Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy. Neurobiology of Disease, 160: 105529. doi: 10.1016/j.nbd.2021.105529
[4]	Carlson J, Li JZ, Zöllner S. 2018. Helmsman: fast and efficient mutation signature analysis for massive sequencing datasets. BMC Genomics, 19(1): 845. doi: 10.1186/s12864-018-5264-y
[5]	Chen JC, Lee G, Fanous AH, et al. 2011. Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia. Schizophrenia Research, 131(1–3): 43–51.
[6]	Chen XY, Schulz-Trieglaff O, Shaw R, et al. 2016. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics, 32(8): 1220−1222. doi: 10.1093/bioinformatics/btv710
[7]	Coe BP, Witherspoon K, Rosenfeld JA, et al. 2014. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature Genetics, 46(10): 1063−1071. doi: 10.1038/ng.3092
[8]	Cooper GM, Coe BP, Girirajan S, et al. 2011. A copy number variation morbidity map of developmental delay. Nature Genetics, 43(9): 838−846. doi: 10.1038/ng.909
[9]	Ekenstedt KJ, Patterson EE, Mickelson JR. 2012. Canine epilepsy genetics. Mammalian Genome, 23(1–2): 28–39.
[10]	Ellis CA, Petrovski S, Berkovic SF. 2020. Epilepsy genetics: clinical impacts and biological insights. The Lancet Neurology, 19(1): 93−100. doi: 10.1016/S1474-4422(19)30269-8
[11]	Gardiner RM. 2000. Impact of our understanding of the genetic aetiology of epilepsy. Journal of Neurology, 247(5): 327−334. doi: 10.1007/s004150050598
[12]	Grzybowska EA. 2012. Human intronless genes: functional groups, associated diseases, evolution, and mRNA processing in absence of splicing. Biochemical and Biophysical Research Communications, 424(1): 1−6. doi: 10.1016/j.bbrc.2012.06.092
[13]	Hardies K, Weckhuysen S, De Jonghe P, et al. 2016. Lessons learned from gene identification studies in Mendelian epilepsy disorders. European Journal of Human Genetics, 24(7): 961−967. doi: 10.1038/ejhg.2015.251
[14]	Helbig I, Mefford HC, Sharp AJ, et al. 2009. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics, 41(2): 160−162. doi: 10.1038/ng.292
[15]	Homman-Ludiye J, Bourne JA. 2020. The marmoset: the next frontier in understanding the development of the human brain. ILAR Journal, 61(2–3): 248–259.
[16]	Hsu CY, Lee KT, Sun TY, et al. 2021. WWOX and its binding proteins in neurodegeneration. Cells, 10(7): 1781. doi: 10.3390/cells10071781
[17]	Iacomino M, Baldassari S, Tochigi Y, et al. 2020. Loss of Wwox perturbs neuronal migration and impairs early cortical development. Frontiers in Neuroscience, 14: 644. doi: 10.3389/fnins.2020.00644
[18]	Johannsen J, Kortüm F, Rosenberger G, et al. 2018. A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay. Neurogenetics, 19(3): 151−156. doi: 10.1007/s10048-018-0549-5
[19]	Kishi N, Sato K, Sasaki E, et al. 2014. Common marmoset as a new model animal for neuroscience research and genome editing technology. Development, Growth & Differentiation, 56(1): 53−62.
[20]	Kos MZ, Carless MA, Blondell L, et al. 2021. Whole genome sequence data from captive baboons implicate RBFOX1 in epileptic seizure risk. Frontiers in Genetics, 12: 714282. doi: 10.3389/fgene.2021.714282
[21]	Kulyté A, Aman A, Strawbridge RJ, et al. 2022. Genome-wide association study identifies genetic loci associated with fat cell number and overlap with genetic risk loci for type 2 diabetes. Diabetes, 71(6): 1350−1362. doi: 10.2337/db21-0804
[22]	Leu C, Stevelink R, Smith AW, et al. 2019. Polygenic burden in focal and generalized epilepsies. Brain, 142(11): 3473−3481. doi: 10.1093/brain/awz292
[23]	Li H. 2011. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics, 27(21): 2987−2993. doi: 10.1093/bioinformatics/btr509
[24]	Li H. 2013. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv,doi: arXiv:1303.3997.
[25]	Li H, Handsaker B, Wysoker A, et al. 2009. The sequence alignment/map format and SAMtools. Bioinformatics, 25(16): 2078−2079. doi: 10.1093/bioinformatics/btp352
[26]	Li MY, Boehnke M, Abecasis GR. 2005. Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal. The American Journal of Human Genetics, 76(6): 934−949. doi: 10.1086/430277
[27]	Li MY, Boehnke M, Abecasis GR. 2006. Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. The American Journal of Human Genetics, 78(5): 778−792. doi: 10.1086/503711
[28]	Liu ZP, Xiang YQ, Sun GH. 2013. The KCTD family of proteins: structure, function, disease relevance. Cell & Bioscience, 3(1): 45.
[29]	Malukiewicz J, Boere V, De Oliveira MAB, et al. 2020. An introduction to the Callithrix genus and overview of recent advances in marmoset research. ILAR Journal, 61(2–3): 110–138.
[30]	Manichaikul A, Mychaleckyj JC, Rich SS, et al. 2010. Robust relationship inference in genome-wide association studies. Bioinformatics, 26(22): 2867−2873. doi: 10.1093/bioinformatics/btq559
[31]	Mao YF, Economo EP, Satoh N. 2018. The roles of introgression and climate change in the rise to dominance of Acropora corals. Current Biology, 28(21): 3373−3382.e5. doi: 10.1016/j.cub.2018.08.061
[32]	Marshall GF, Gonzalez-Sulser A, Abbott CM. 2021. Modelling epilepsy in the mouse: challenges and solutions. Disease Models & Mechanisms, 14(3): dmm047449.
[33]	Martin M, Patterson M, Garg S, et al. 2016. WhatsHap: fast and accurate read-based phasing. BioRxiv, doi: https://doi.org/10.1101/085050.
[34]	McKenna A, Hanna M, Banks E, et al. 2010. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research, 20(9): 1297−1303. doi: 10.1101/gr.107524.110
[35]	Moreau C, Rébillard RM, Wolking S, et al. 2020. Polygenic risk scores of several subtypes of epilepsies in a founder population. Neurology Genetics, 6(3): e416. doi: 10.1212/NXG.0000000000000416
[36]	Mullen SA, Berkovic SF, the ILAE Genetics Commission. 2018. Genetic generalized epilepsies. Epilepsia, 59(6): 1148−1153. doi: 10.1111/epi.14042
[37]	National Academies of Sciences, Engineering, and Medicine. 2019. Care, use, and welfare of marmosets as animal models for gene editing-based biomedical research. In: Proceedings of a Workshop. Washington: The National Academies Press.
[38]	Nishijima K, Saitoh R, Tanaka S, et al. 2012. Life span of common marmoset (Callithrix jacchus) at CLEA Japan breeding colony. Biogerontology, 13(4): 439−443. doi: 10.1007/s10522-012-9388-1
[39]	Okano H, Mitra P. 2015. Brain-mapping projects using the common marmoset. Neuroscience Research, 93: 3−7. doi: 10.1016/j.neures.2014.08.014
[40]	Okano H, Sasaki E, Yamamori T, et al. 2016. Brain/MINDS: a Japanese national brain project for marmoset neuroscience. Neuron, 92(3): 582−590. doi: 10.1016/j.neuron.2016.10.018
[41]	Patterson M, Marschall T, Pisanti N, et al. 2015. WhatsHap: weighted haplotype assembly for future-generation sequencing reads. Journal of Computational Biology, 22(6): 498−509. doi: 10.1089/cmb.2014.0157
[42]	Pedersen B. 2018. Smoove: structural variant calling and genotyping with existing tools, but, smoothly.https://github.com/brentp/smoove.
[43]	Plani-Lam JHC, Chow TC, Siu KL, et al. 2015. PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling. The International Journal of Biochemistry & Cell Biology, 61: 53−62.
[44]	Poo MM, Du JL, Ip NY, et al. 2016. China brain project: basic neuroscience, brain diseases, and brain-inspired computing. Neuron, 92(3): 591−596. doi: 10.1016/j.neuron.2016.10.050
[45]	Purcell S, Neale B, Todd-Brown K, et al. 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics, 81(3): 559−575. doi: 10.1086/519795
[46]	Repudi S, Steinberg DJ, Elazar N, et al. 2021. Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects. Brain, 144(10): 3061−3077. doi: 10.1093/brain/awab174
[47]	Robinson R, Gardiner M. 2004. Molecular basis of Mendelian idiopathic epilepsies. Annals of Medicine, 36(2): 89−97. doi: 10.1080/07853890310019952
[48]	Ross CN, French JA, Ortí G. 2007. Germ-line chimerism and paternal care in marmosets (Callithrix kuhlii). Proceedings of the National Academy of Sciences of the United States of America, 104(15): 6278−6282.
[49]	Sato K, Kuroki Y, Kumita W, et al. 2015. Resequencing of the common marmoset genome improves genome assemblies and gene-coding sequence analysis. Scientific Reports, 5: 16894. doi: 10.1038/srep16894
[50]	Scharfman HE. 2007. The neurobiology of epilepsy. Current Neurology and Neuroscience Reports, 7(4): 348−354. doi: 10.1007/s11910-007-0053-z
[51]	Shimogori T, Abe A, Go Y, et al. 2018. Digital gene atlas of neonate common marmoset brain. Neuroscience Research, 128: 1−13. doi: 10.1016/j.neures.2017.10.009
[52]	Shorvon SD. 2011. The etiologic classification of epilepsy. Epilepsia, 52(6): 1052−1057. doi: 10.1111/j.1528-1167.2011.03041.x
[53]	Stewart I. 2010. Environmental risk factors for temporal lobe epilepsy–Is prenatal exposure to the marine algal neurotoxin domoic acid a potentially preventable cause?. Medical Hypotheses, 74(3): 466−481. doi: 10.1016/j.mehy.2009.10.018
[54]	Sweeney CG, Curran E, Westmoreland SV, et al. 2012. Quantitative molecular assessment of chimerism across tissues in marmosets and tamarins. BMC Genomics, 13: 98. doi: 10.1186/1471-2164-13-98
[55]	Teng XC, Aouacheria A, Lionnard L, et al. 2019. KCTD: a new gene family involved in neurodevelopmental and neuropsychiatric disorders. CNS Neuroscience & Therapeutics, 25(7): 887−902.
[56]	The Marmoset Genome Sequencing and Analysis Consortium. 2014. The common marmoset genome provides insight into primate biology and evolution. Nature Genetics, 46(8): 850−857. doi: 10.1038/ng.3042
[57]	Thijs RD, Surges R, O'Brien TJ, et al. 2019. Epilepsy in adults. The Lancet, 393(10172): 689−701. doi: 10.1016/S0140-6736(18)32596-0
[58]	Thomas RH, Berkovic SF. 2014. The hidden genetics of epilepsy—a clinically important new paradigm. Nature Reviews Neurology, 10(5): 283−292. doi: 10.1038/nrneurol.2014.62
[59]	Usui D, Shimada S, Shimojima K, et al. 2013. Interstitial duplication of 2q32.1–q33.3 in a patient with epilepsy, developmental delay, and autistic behavior. American Journal of Medical Genetics Part A, 161(5): 1078−1084. doi: 10.1002/ajmg.a.35679
[60]	Warren WC, Harris RA, Haukness M, et al. 2020. Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility. Science, 370(6523): eabc6617. doi: 10.1126/science.abc6617
[61]	Wielaender F, Sarviaho R, James F, et al. 2017. Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1. Proceedings of the National Academy of Sciences of the United States of America, 114(10): 2669−2674.
[62]	Yang CT, Zhou Y, Marcus S, et al. 2021. Evolutionary and biomedical insights from a marmoset diploid genome assembly. Nature, 594(7862): 227−233. doi: 10.1038/s41586-021-03535-x
[63]	Yang XY, Chen ZT, Wang ZY, et al. 2022. A natural marmoset model of genetic generalized epilepsy. Molecular Brain, 15(1): 16. doi: 10.1186/s13041-022-00901-2
[64]	Ye J, Coulouris G, Zaretskaya I, et al. 2012. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics, 13: 134. doi: 10.1186/1471-2105-13-134
[65]	Youlatos D. 2009. The smallest anthropoids. Journal of Long-Term Effects of Medical Implants, 18(2): 175−179.