---
OA_place: publisher
OA_type: hybrid
_id: '20848'
abstract:
- lang: eng
text: 'Genetic variation that influences complex disease susceptibility is introduced
into the population by mutation and removed by natural selection and genetic drift.
This mutation–selection–drift balance (MSDB) shapes the prevalence of a disease
and its genetic architecture. To date, however, MSDB has been modeled only for
monogenic (Mendelian) diseases. Here, we develop an MSDB model for complex disease
susceptibility: we assume that genotype relates to disease risk according to the
canonical liability threshold model and that the selection on variants affecting
risk stems from the fitness cost of the disease. We focus on diseases that are
highly polygenic, entail a substantial fitness cost, and are neither extremely
common in the population nor exceedingly rare. The comparison of model predictions
with genome-wide association studies and other observations in humans indicates
that common genetic variation affecting complex disease susceptibility is little
affected by directional selection and instead shaped by pleiotropic stabilizing
selection on other traits. In turn, directional selection may exert a more substantial
effect on rare, large-effect variants. Our results also suggest that current estimates
of disease heritability are likely biased. The model thus provides a better understanding
of the evolutionary processes that shape the architecture and prevalence of complex
diseases.'
acknowledgement: We thank Nick Barton, Magnus Nordborg, John Novembre, Molly Przeworski,
and Himani Sachdeva for many helpful discussions and for comments on the manuscript,
and we thank Joshua Schraiber and 2 anonymous reviewers for comments on the manuscript.
We also thank members of the Sella, Przeworski and Andolfatto labs at Columbia University,
and the Berg, Novembre and Steinrücken labs at the University of Chicago, for feedback
on the work at various stages. This work was completed in part with resources provided
by the University of Chicago's Research Computing Center. This work was supported
by National Institutes of Health F32 grant GM126787 and R35 grant GM151257 to J.J.B.
and National Institutes of Health R01 grant GM115889 to G.S.
article_number: iyaf220
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Jeremy J.
full_name: Berg, Jeremy J.
last_name: Berg
- first_name: Xinyi
full_name: Li, Xinyi
last_name: Li
- first_name: Kellen
full_name: Riall, Kellen
last_name: Riall
- first_name: Laura
full_name: Hayward, Laura
id: fc885ee5-24bf-11eb-ad7b-bcc5104c0c1b
last_name: Hayward
- first_name: Guy
full_name: Sella, Guy
last_name: Sella
citation:
ama: Berg JJ, Li X, Riall K, Hayward L, Sella G. Mutation–selection–drift balance
models of complex diseases. Genetics. 2025;231(4). doi:10.1093/genetics/iyaf220
apa: Berg, J. J., Li, X., Riall, K., Hayward, L., & Sella, G. (2025). Mutation–selection–drift
balance models of complex diseases. Genetics. Oxford University Press.
https://doi.org/10.1093/genetics/iyaf220
chicago: Berg, Jeremy J., Xinyi Li, Kellen Riall, Laura Hayward, and Guy Sella.
“Mutation–Selection–Drift Balance Models of Complex Diseases.” Genetics.
Oxford University Press, 2025. https://doi.org/10.1093/genetics/iyaf220.
ieee: J. J. Berg, X. Li, K. Riall, L. Hayward, and G. Sella, “Mutation–selection–drift
balance models of complex diseases,” Genetics, vol. 231, no. 4. Oxford
University Press, 2025.
ista: Berg JJ, Li X, Riall K, Hayward L, Sella G. 2025. Mutation–selection–drift
balance models of complex diseases. Genetics. 231(4), iyaf220.
mla: Berg, Jeremy J., et al. “Mutation–Selection–Drift Balance Models of Complex
Diseases.” Genetics, vol. 231, no. 4, iyaf220, Oxford University Press,
2025, doi:10.1093/genetics/iyaf220.
short: J.J. Berg, X. Li, K. Riall, L. Hayward, G. Sella, Genetics 231 (2025).
date_created: 2025-12-21T23:01:34Z
date_published: 2025-12-01T00:00:00Z
date_updated: 2025-12-29T11:29:16Z
day: '01'
ddc:
- '570'
department:
- _id: NiBa
doi: 10.1093/genetics/iyaf220
external_id:
pmid:
- '41073879'
file:
- access_level: open_access
checksum: b02eb6b78028b8bef435edc8435a8468
content_type: application/pdf
creator: dernst
date_created: 2025-12-29T11:27:51Z
date_updated: 2025-12-29T11:27:51Z
file_id: '20863'
file_name: 2025_Genetics_Berg.pdf
file_size: 1182339
relation: main_file
success: 1
file_date_updated: 2025-12-29T11:27:51Z
fulldoi: https://doi.org/10.1093/genetics/iyaf220
has_accepted_license: '1'
intvolume: ' 231'
issue: '4'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
pmid: 1
publication: Genetics
publication_identifier:
eissn:
- 1943-2631
issn:
- 0016-6731
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: Mutation–selection–drift balance models of complex diseases
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 231
year: '2025'
...
---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '20330'
abstract:
- lang: eng
text: The evolution of sexual dimorphism (the difference in average trait values
between females and males, SD), is often thought to be constrained by shared genetic
architecture between the sexes. Indeed, it is commonly expected that SD should
negatively correlate with the intersex correlation (the genetic correlation between
effects of segregating variants in females and males, r fm), either because (1)
traits with ancestrally low r fm are less constrained in their ability to respond
to sex-specific selection and thus evolve to be more dimorphic, or because (2)
sex-specific selection, driving sexual dimorphism evolution, also acts to reduce
r fm. Despite the intuitive appeal and prominence of these ideas, their generality
and the conditions in which they hold remain unclear. Here, we develop models
incorporating sex-specific stabilizing selection, mutation and genetic drift to
examine the relationship between r fm and SD. We show that the two commonly-discussed
mechanisms with the potential to generate a negative correlation between SD and
r fm could just as easily generate a positive association, since the standard
line of reasoning hinges on a hidden assumption that sex-specific adaptation more
frequently favors increased dimorphism than reduced dimorphism. Our results provide,
to our knowledge, the first mechanistic framework for understanding the conditions
under which a correlation between r fm and SD may arise and offer a compelling
explanation for inconsistent empirical evidence. We also make the intriguing observation
that—even when selection between the two sexes is identical—drift generates nonzero
SD. We quantify this effect and discuss its significance.
acknowledgement: We thank Tim Connallon for useful discussions and correspondence,
Himani Sachdeva and Nick Barton for comments on the manuscript and the Scientific
Computing unit at ISTA for technical support. GP is the recipient of a DOC Fellowship
of the Austrian Academy of Sciences at the Institute of Science and Technology Austria
(DOC 25817) and received funding from the European Union’s Horizon 2020 research
and innovation program under the Marie Skłodowska-Curie Grant (agreement no. 665385).
LH received funding from the European Research Council, under the HaplotypeStructure
Grant (grant no. 101055327) to Nick Barton.
article_number: iyaf175
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Gemma
full_name: Puixeu Sala, Gemma
id: 33AB266C-F248-11E8-B48F-1D18A9856A87
last_name: Puixeu Sala
orcid: 0000-0001-8330-1754
- first_name: Laura
full_name: Hayward, Laura
id: fc885ee5-24bf-11eb-ad7b-bcc5104c0c1b
last_name: Hayward
citation:
ama: 'Puixeu Sala G, Hayward L. The relationship between sexual dimorphism and intersex
correlation: Do models support intuition? Genetics. 2025;231(3). doi:10.1093/genetics/iyaf175'
apa: 'Puixeu Sala, G., & Hayward, L. (2025). The relationship between sexual
dimorphism and intersex correlation: Do models support intuition? Genetics.
Oxford University Press. https://doi.org/10.1093/genetics/iyaf175'
chicago: 'Puixeu Sala, Gemma, and Laura Hayward. “The Relationship between Sexual
Dimorphism and Intersex Correlation: Do Models Support Intuition?” Genetics.
Oxford University Press, 2025. https://doi.org/10.1093/genetics/iyaf175.'
ieee: 'G. Puixeu Sala and L. Hayward, “The relationship between sexual dimorphism
and intersex correlation: Do models support intuition?,” Genetics, vol.
231, no. 3. Oxford University Press, 2025.'
ista: 'Puixeu Sala G, Hayward L. 2025. The relationship between sexual dimorphism
and intersex correlation: Do models support intuition? Genetics. 231(3), iyaf175.'
mla: 'Puixeu Sala, Gemma, and Laura Hayward. “The Relationship between Sexual Dimorphism
and Intersex Correlation: Do Models Support Intuition?” Genetics, vol.
231, no. 3, iyaf175, Oxford University Press, 2025, doi:10.1093/genetics/iyaf175.'
short: G. Puixeu Sala, L. Hayward, Genetics 231 (2025).
corr_author: '1'
date_created: 2025-09-10T05:48:04Z
date_published: 2025-11-01T00:00:00Z
date_updated: 2026-01-05T13:04:07Z
day: '01'
ddc:
- '570'
department:
- _id: BeVi
- _id: NiBa
doi: 10.1093/genetics/iyaf175
ec_funded: 1
external_id:
isi:
- '001598595000001'
file:
- access_level: open_access
checksum: bbb73bbf8617812d4d8db4af92be9538
content_type: application/pdf
creator: dernst
date_created: 2026-01-05T13:03:18Z
date_updated: 2026-01-05T13:03:18Z
file_id: '20946'
file_name: 2025_Genetics_Puixeu.pdf
file_size: 1550562
relation: main_file
success: 1
file_date_updated: 2026-01-05T13:03:18Z
fulldoi: https://doi.org/10.1093/genetics/iyaf175
has_accepted_license: '1'
intvolume: ' 231'
isi: 1
issue: '3'
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
project:
- _id: 9B9DFC9E-BA93-11EA-9121-9846C619BF3A
grant_number: '25817'
name: 'Sexual conflict: resolution, constraints and biomedical implications'
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '665385'
name: International IST Doctoral Program
- _id: bd6958e0-d553-11ed-ba76-86eba6a76c00
grant_number: '101055327'
name: Understanding the evolution of continuous genomes
publication: Genetics
publication_identifier:
issn:
- 1943-2631
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'The relationship between sexual dimorphism and intersex correlation: Do models
support intuition?'
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 231
year: '2025'
...
---
_id: '12157'
abstract:
- lang: eng
text: 'Polygenic adaptation is thought to be ubiquitous, yet remains poorly understood.
Here, we model this process analytically, in the plausible setting of a highly
polygenic, quantitative trait that experiences a sudden shift in the fitness optimum.
We show how the mean phenotype changes over time, depending on the effect sizes
of loci that contribute to variance in the trait, and characterize the allele
dynamics at these loci. Notably, we describe the two phases of the allele dynamics:
The first is a rapid phase, in which directional selection introduces small frequency
differences between alleles whose effects are aligned with or opposed to the shift,
ultimately leading to small differences in their probability of fixation during
a second, longer phase, governed by stabilizing selection. As we discuss, key
results should hold in more general settings and have important implications for
efforts to identify the genetic basis of adaptation in humans and other species.'
acknowledgement: "We thank Guy Amster, Jeremy Berg, Nick Barton, Yuval Simons and
Molly Przeworski for many helpful discussions, and Jeremy Berg, Graham Coop, Joachim
Hermisson, Guillaume Martin, Will Milligan, Peter Ralph, Yuval Simons, Leo Speidel
and Molly Przeworski for comments on the manuscript.\r\nNational Institutes of Health
GM115889 Laura Katharine Hayward Guy Sella \r\nNational Institutes of Health GM121372
Laura Katharine Hayward"
article_number: '66697'
article_processing_charge: No
article_type: original
author:
- first_name: Laura
full_name: Hayward, Laura
id: fc885ee5-24bf-11eb-ad7b-bcc5104c0c1b
last_name: Hayward
- first_name: Guy
full_name: Sella, Guy
last_name: Sella
citation:
ama: Hayward L, Sella G. Polygenic adaptation after a sudden change in environment.
eLife. 2022;11. doi:10.7554/elife.66697
apa: Hayward, L., & Sella, G. (2022). Polygenic adaptation after a sudden change
in environment. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.66697
chicago: Hayward, Laura, and Guy Sella. “Polygenic Adaptation after a Sudden Change
in Environment.” ELife. eLife Sciences Publications, 2022. https://doi.org/10.7554/elife.66697.
ieee: L. Hayward and G. Sella, “Polygenic adaptation after a sudden change in environment,”
eLife, vol. 11. eLife Sciences Publications, 2022.
ista: Hayward L, Sella G. 2022. Polygenic adaptation after a sudden change in environment.
eLife. 11, 66697.
mla: Hayward, Laura, and Guy Sella. “Polygenic Adaptation after a Sudden Change
in Environment.” ELife, vol. 11, 66697, eLife Sciences Publications, 2022,
doi:10.7554/elife.66697.
short: L. Hayward, G. Sella, ELife 11 (2022).
corr_author: '1'
date_created: 2023-01-12T12:09:00Z
date_published: 2022-09-26T00:00:00Z
date_updated: 2024-10-09T21:03:38Z
day: '26'
ddc:
- '570'
department:
- _id: NiBa
doi: 10.7554/elife.66697
external_id:
isi:
- '000890735600001'
file:
- access_level: open_access
checksum: 28de155b231ac1c8d4501c98b2fb359a
content_type: application/pdf
creator: dernst
date_created: 2023-01-24T12:21:32Z
date_updated: 2023-01-24T12:21:32Z
file_id: '12363'
file_name: 2022_eLife_Hayward.pdf
file_size: 18935612
relation: main_file
success: 1
file_date_updated: 2023-01-24T12:21:32Z
fulldoi: https://doi.org/10.7554/elife.66697
has_accepted_license: '1'
intvolume: ' 11'
isi: 1
keyword:
- General Immunology and Microbiology
- General Biochemistry
- Genetics and Molecular Biology
- General Medicine
- General Neuroscience
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
publication: eLife
publication_identifier:
eissn:
- 2050-084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: Polygenic adaptation after a sudden change in environment
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 11
year: '2022'
...