Rate of de novo mutations and the importance of father's age to disease risk

被引：1430

作者：

Kong, Augustine ^{[1
]}

Frigge, Michael L. ^{[1
]}

Masson, Gisli ^{[1
]}

Besenbacher, Soren ^{[1
,2
]}

Sulem, Patrick ^{[1
]}

Magnusson, Gisli ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Jonasdottir, Adalbjorg ^{[1
]}

Wong, Wendy S. W. ^{[3
]}

Sigurdsson, Gunnar ^{[1
]}

Walters, G. Bragi ^{[1
]}

Steinberg, Stacy ^{[1
]}

Helgason, Hannes ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Gudbjartsson, Daniel F. ^{[1
]}

Helgason, Agnar ^{[1
]}

Magnusson, Olafur Th. ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
,4
]}

Stefansson, Kari ^{[1
,4
]}

机构：

[1] deCODE Genet, IS-101 Reykjavik, Iceland

[2] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark

[3] Illumina Cambridge Ltd, Saffron Walden CB10 1XL, Essex, England

[4] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

来源：

NATURE | 2012年 / 488卷 / 7412期

基金：

美国国家卫生研究院;

关键词：

AUTISM SPECTRUM DISORDERS; SCHIZOPHRENIA; HUMANS; CONSEQUENCES; NUCLEOTIDE; PATTERNS; NRXN1;

D O I：

10.1038/nature11396

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 x 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.

引用

页码：471 / 475

页数：5

共 27 条

[11] Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia [J].

Kirov, George ;

Gumus, Dilihan ;

Chen, Wei ;

Norton, Nadine ;

Georgieva, Lyudmila ;

Sari, Murat ;

O'Donovan, Michael C. ;

Erdogan, Fikret ;

Owen, Michael J. ;

Ropers, Hans-Hilger ;

Ullmann, Reinhard .

HUMAN MOLECULAR GENETICS, 2008, 17 (03) :458-465

[12] Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases [J].

Kondrashov, AS .

HUMAN MUTATION, 2003, 21 (01) :12-27

[13] Recombination rate and reproductive success in humans [J].

Kong, A ;

Barnard, J ;

Gudbjartsson, DF ;

Thorleifsson, G ;

Jonsdottir, G ;

Sigurdardottir, S ;

Richardsson, B ;

Jonsdottir, J ;

Thorgeirsson, T ;

Frigge, ML ;

Lamb, NE ;

Sherman, S ;

Gulcher, JR ;

Stefansson, K .

NATURE GENETICS, 2004, 36 (11) :1203-1206

[14] Copy Number Variants in Schizophrenia: Confirmation of Five Previous Findings and New Evidence for 3q29 Microdeletions and VIPR2 Duplications [J].

Levinson, Douglas F. ;

Duan, Jubao ;

Oh, Sang ;

Wang, Kai ;

Sanders, Alan R. ;

Shi, Jianxin ;

Zhang, Nancy ;

Mowry, Bryan J. ;

Olincy, Ann ;

Amin, Farooq ;

Cloninger, C. Robert ;

Silverman, Jeremy M. ;

Buccola, Nancy G. ;

Byerley, William F. ;

Black, Donald W. ;

Kendler, Kenneth S. ;

Freedman, Robert ;

Dudbridge, Frank ;

Pe'er, Itsik ;

Hakonarson, Hakon ;

Bergen, Sarah E. ;

Fanous, Ayman H. ;

Holmans, Peter A. ;

Gejman, Pablo V. .

AMERICAN JOURNAL OF PSYCHIATRY, 2011, 168 (03) :302-316

[15] Fast and accurate short read alignment with Burrows-Wheeler transform [J].

Li, Heng ;

Durbin, Richard .

BIOINFORMATICS, 2009, 25 (14) :1754-1760

[16] Rate, molecular spectrum, and consequences of human mutation [J].

Lynch, Michael .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (03) :961-968

[17] Paternal factors and schizophrenia risk: De novo mutations and imprinting [J].

Malaspina, D .

SCHIZOPHRENIA BULLETIN, 2001, 27 (03) :379-393

[18] The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data [J].

McKenna, Aaron ;

Hanna, Matthew ;

Banks, Eric ;

Sivachenko, Andrey ;

Cibulskis, Kristian ;

Kernytsky, Andrew ;

Garimella, Kiran ;

Altshuler, David ;

Gabriel, Stacey ;

Daly, Mark ;

DePristo, Mark A. .

GENOME RESEARCH, 2010, 20 (09) :1297-1303

[19]

Nachman MW, 2000, GENETICS, V156, P297

[20] Patterns and rates of exonic de novo mutations in autism spectrum disorders [J].

Neale, Benjamin M. ;

Kou, Yan ;

Liu, Li ;

Ma'ayan, Avi ;

Samocha, Kaitlin E. ;

Sabo, Aniko ;

Lin, Chiao-Feng ;

Stevens, Christine ;

Wang, Li-San ;

Makarov, Vladimir ;

Polak, Paz ;

Yoon, Seungtai ;

Maguire, Jared ;

Crawford, Emily L. ;

Campbell, Nicholas G. ;

Geller, Evan T. ;

Valladares, Otto ;

Schafer, Chad ;

Liu, Han ;

Zhao, Tuo ;

Cai, Guiqing ;

Lihm, Jayon ;

Dannenfelser, Ruth ;

Jabado, Omar ;

Peralta, Zuleyma ;

Nagaswamy, Uma ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Newsham, Irene ;

Wu, Yuanqing ;

Lewis, Lora ;

Han, Yi ;

Voight, Benjamin F. ;

Lim, Elaine ;

Rossin, Elizabeth ;

Kirby, Andrew ;

Flannick, Jason ;

Fromer, Menachem ;

Shakir, Khalid ;

Fennell, Tim ;

Garimella, Kiran ;

Banks, Eric ;

Poplin, Ryan ;

Gabriel, Stacey ;

DePristo, Mark ;

Wimbish, Jack R. ;

Boone, Braden E. ;

Levy, Shawn E. ;

Betancur, Catalina ;

Sunyaev, Shamil .

NATURE, 2012, 485 (7397) :242-U129

← 1 2 3 →