The origins and functional effects of postzygotic mutations throughout the human life span

Nicole B. Rockweiler; Avinash Ramu; Liina Nagirnaja; Wing H. Wong; Michiel J. Noordam; Casey W. Drubin; Ni Huang; Brian Miller; Ellen Z. Todres; Katinka A. Vigh-Conrad; Antonino Zito; Kerrin S. Small; Kristin G. Ardlie; Barak A. Cohen; Donald F. Conrad

doi:10.1126/science.abn7113

The origins and functional effects of postzygotic mutations throughout the human life span

Nicole B. Rockweiler, Avinash Ramu, Liina Nagirnaja, Wing H. Wong, Michiel J. Noordam, Casey W. Drubin, Ni Huang, Brian Miller, Ellen Z. Todres, Katinka A. Vigh-Conrad, Antonino Zito, Kerrin S. Small, Kristin G. Ardlie, Barak A. Cohen, Donald F. Conrad

Oregon National Primate Research Center

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.

Original language	English (US)
Article number	eabn7113
Journal	Science
Volume	380
Issue number	6641
DOIs	https://doi.org/10.1126/science.abn7113
State	Published - Apr 14 2023

ASJC Scopus subject areas

General

Access to Document

10.1126/science.abn7113

Cite this

Rockweiler, N. B., Ramu, A., Nagirnaja, L., Wong, W. H., Noordam, M. J., Drubin, C. W., Huang, N., Miller, B., Todres, E. Z., Vigh-Conrad, K. A., Zito, A., Small, K. S., Ardlie, K. G., Cohen, B. A., & Conrad, D. F. (2023). The origins and functional effects of postzygotic mutations throughout the human life span. Science, 380(6641), Article eabn7113. https://doi.org/10.1126/science.abn7113

@article{b9ab96b3db2b4336a60f8808ebef56ef,

title = "The origins and functional effects of postzygotic mutations throughout the human life span",

abstract = "Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.",

author = "Rockweiler, {Nicole B.} and Avinash Ramu and Liina Nagirnaja and Wong, {Wing H.} and Noordam, {Michiel J.} and Drubin, {Casey W.} and Ni Huang and Brian Miller and Todres, {Ellen Z.} and Vigh-Conrad, {Katinka A.} and Antonino Zito and Small, {Kerrin S.} and Ardlie, {Kristin G.} and Cohen, {Barak A.} and Conrad, {Donald F.}",

year = "2023",

month = apr,

day = "14",

doi = "10.1126/science.abn7113",

language = "English (US)",

volume = "380",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6641",

}

TY - JOUR

T1 - The origins and functional effects of postzygotic mutations throughout the human life span

AU - Rockweiler, Nicole B.

AU - Ramu, Avinash

AU - Nagirnaja, Liina

AU - Wong, Wing H.

AU - Noordam, Michiel J.

AU - Drubin, Casey W.

AU - Huang, Ni

AU - Miller, Brian

AU - Todres, Ellen Z.

AU - Vigh-Conrad, Katinka A.

AU - Zito, Antonino

AU - Small, Kerrin S.

AU - Ardlie, Kristin G.

AU - Cohen, Barak A.

AU - Conrad, Donald F.

PY - 2023/4/14

Y1 - 2023/4/14

N2 - Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.

AB - Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.

UR - http://www.scopus.com/inward/record.url?scp=85152444910&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85152444910&partnerID=8YFLogxK

U2 - 10.1126/science.abn7113

DO - 10.1126/science.abn7113

M3 - Article

C2 - 37053313

AN - SCOPUS:85152444910

SN - 0036-8075

VL - 380

JO - Science

JF - Science

IS - 6641

M1 - eabn7113

ER -

The origins and functional effects of postzygotic mutations throughout the human life span

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this