. 2023 Apr 28;380(6643):eabn2937.

doi: 10.1126/science.abn2937. Epub 2023 Apr 28.

Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Patrick F Sullivan^#^{1

2}, Jennifer R S Meadows^#³, Steven Gazal^#^{4

5}, BaDoi N Phan⁶, Xue Li^{7

8}, Diane P Genereux⁷, Michael X Dong³, Matteo Bianchi³, Gregory Andrews⁷, Sharadha Sakthikumar^{3

8}, Jessika Nordin³, Ananya Roy⁹, Matthew J Christmas³, Voichita D Marinescu³, Chao Wang³, Ola Wallerman³, James Xue^{8

10}, Shuyang Yao², Quan Sun¹, Jin Szatkiewicz¹, Jia Wen¹, Laura M Huckins¹¹, Alyssa Lawler^{12

13}, Kathleen C Keough^{14

15}, Zhili Zheng¹⁶, Jian Zeng¹⁶, Naomi R Wray¹⁶, Yun Li¹, Jessica Johnson¹¹, Jiawen Chen¹⁷; Zoonomia Consortium§; Benedict Paten¹⁸, Steven K Reilly¹⁹, Graham M Hughes²⁰, Zhiping Weng⁷, Katherine S Pollard^{14

15

21}, Andreas R Pfenning^{6

12}, Karin Forsberg-Nilsson^{9

22}, Elinor K Karlsson^#^{7

8

23}, Kerstin Lindblad-Toh^#^{3

8}

Collaborators, Affiliations

Collaborators

Zoonomia Consortium§:
Gregory Andrews, Joel C Armstrong, Matteo Bianchi, Bruce W Birren, Kevin R Bredemeyer, Ana M Breit, Matthew J Christmas, Hiram Clawson, Joana Damas, Federica Di Palma, Mark Diekhans, Michael X Dong, Eduardo Eizirik, Kaili Fan, Cornelia Fanter, Nicole M Foley, Karin Forsberg-Nilsson, Carlos J Garcia, John Gatesy, Steven Gazal, Diane P Genereux, Linda Goodman, Jenna Grimshaw, Michaela K Halsey, Andrew J Harris, Glenn Hickey, Michael Hiller, Allyson G Hindle, Robert M Hubley, Graham M Hughes, Jeremy Johnson, David Juan, Irene M Kaplow, Elinor K Karlsson, Kathleen C Keough, Bogdan Kirilenko, Klaus-Peter Koepfli, Jennifer M Korstian, Amanda Kowalczyk, Sergey V Kozyrev, Alyssa J Lawler, Colleen Lawless, Thomas Lehmann, Danielle L Levesque, Harris A Lewin, Xue Li, Abigail Lind, Kerstin Lindblad-Toh, Ava Mackay-Smith, Voichita D Marinescu, Tomas Marques-Bonet, Victor C Mason, Jennifer R S Meadows, Wynn K Meyer, Jill E Moore, Lucas R Moreira, Diana D Moreno-Santillan, Kathleen M Morrill, Gerard Muntané, William J Murphy, Arcadi Navarro, Martin Nweeia, Sylvia Ortmann, Austin Osmanski, Benedict Paten, Nicole S Paulat, Andreas R Pfenning, BaDoi N Phan, Katherine S Pollard, Henry E Pratt, David A Ray, Steven K Reilly, Jeb R Rosen, Irina Ruf, Louise Ryan, Oliver A Ryder, Pardis C Sabeti, Daniel E Schäffer, Aitor Serres, Beth Shapiro, Arian F A Smit, Mark Springer, Chaitanya Srinivasan, Cynthia Steiner, Jessica M Storer, Kevin A M Sullivan, Patrick F Sullivan, Elisabeth Sundström, Megan A Supple, Ross Swofford, Joy-El Talbot, Emma Teeling, Jason Turner-Maier, Alejandro Valenzuela, Franziska Wagner, Ola Wallerman, Chao Wang, Juehan Wang, Zhiping Weng, Aryn P Wilder, Morgan E Wirthlin, James R Xue, Xiaomeng Zhang

Affiliations

¹ Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden.
³ Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.
⁴ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁶ Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
⁷ Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁹ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.
¹⁰ Center for System Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
¹¹ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹³ Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹⁴ Gladstone Institutes, San Francisco, CA 94158, USA.
¹⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.
¹⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
¹⁷ Department of Biostatistics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
¹⁸ UC Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
²⁰ School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland.
²¹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
²² Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK.
²³ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.

^# Contributed equally.

PMID: 37104612
PMCID: PMC10259825
DOI: 10.1126/science.abn2937

Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Patrick F Sullivan et al. Science. 2023.

. 2023 Apr 28;380(6643):eabn2937.

doi: 10.1126/science.abn2937. Epub 2023 Apr 28.

Authors

Collaborators

Zoonomia Consortium§:
Gregory Andrews, Joel C Armstrong, Matteo Bianchi, Bruce W Birren, Kevin R Bredemeyer, Ana M Breit, Matthew J Christmas, Hiram Clawson, Joana Damas, Federica Di Palma, Mark Diekhans, Michael X Dong, Eduardo Eizirik, Kaili Fan, Cornelia Fanter, Nicole M Foley, Karin Forsberg-Nilsson, Carlos J Garcia, John Gatesy, Steven Gazal, Diane P Genereux, Linda Goodman, Jenna Grimshaw, Michaela K Halsey, Andrew J Harris, Glenn Hickey, Michael Hiller, Allyson G Hindle, Robert M Hubley, Graham M Hughes, Jeremy Johnson, David Juan, Irene M Kaplow, Elinor K Karlsson, Kathleen C Keough, Bogdan Kirilenko, Klaus-Peter Koepfli, Jennifer M Korstian, Amanda Kowalczyk, Sergey V Kozyrev, Alyssa J Lawler, Colleen Lawless, Thomas Lehmann, Danielle L Levesque, Harris A Lewin, Xue Li, Abigail Lind, Kerstin Lindblad-Toh, Ava Mackay-Smith, Voichita D Marinescu, Tomas Marques-Bonet, Victor C Mason, Jennifer R S Meadows, Wynn K Meyer, Jill E Moore, Lucas R Moreira, Diana D Moreno-Santillan, Kathleen M Morrill, Gerard Muntané, William J Murphy, Arcadi Navarro, Martin Nweeia, Sylvia Ortmann, Austin Osmanski, Benedict Paten, Nicole S Paulat, Andreas R Pfenning, BaDoi N Phan, Katherine S Pollard, Henry E Pratt, David A Ray, Steven K Reilly, Jeb R Rosen, Irina Ruf, Louise Ryan, Oliver A Ryder, Pardis C Sabeti, Daniel E Schäffer, Aitor Serres, Beth Shapiro, Arian F A Smit, Mark Springer, Chaitanya Srinivasan, Cynthia Steiner, Jessica M Storer, Kevin A M Sullivan, Patrick F Sullivan, Elisabeth Sundström, Megan A Supple, Ross Swofford, Joy-El Talbot, Emma Teeling, Jason Turner-Maier, Alejandro Valenzuela, Franziska Wagner, Ola Wallerman, Chao Wang, Juehan Wang, Zhiping Weng, Aryn P Wilder, Morgan E Wirthlin, James R Xue, Xiaomeng Zhang

Affiliations

¹ Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden.
³ Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.
⁴ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁶ Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
⁷ Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁹ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.
¹⁰ Center for System Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
¹¹ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹³ Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹⁴ Gladstone Institutes, San Francisco, CA 94158, USA.
¹⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.
¹⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
¹⁷ Department of Biostatistics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
¹⁸ UC Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
²⁰ School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland.
²¹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
²² Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK.
²³ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.

^# Contributed equally.

PMID: 37104612
PMCID: PMC10259825
DOI: 10.1126/science.abn2937

Abstract

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

PubMed Disclaimer

Conflict of interest statement

Competing interests: P.F.S. is a consultant and shareholder for Neumora.

Figures

**Fig. 1.. Overview of constraint distribution.**
(A) Evolutionary constraint in multiple genomic partitions. The x axis is the fraction of the genome occupied by a partition, the y axis is the fraction of partition under constraint in placental mammals (purple circles) and primates (blue triangles), and the gray line is the genome mean (0.033). The greatest constraint is found in CDS and key regulatory regions (5′UTRs, ENCODE promoter-like elements, and 3′UTRs). The higher fraction constrained in primates versus mammals is due to different constraint definitions and does not necessarily reflect biology. This figure is a subset of fig. S1 and data from section 4 of the SM, which shows more biotypes, PC gene parts, and regulatory regions. dhs, DNase I hypersensitive sites. (B) Whisker plots of constraint in variants from TOPMed whole-genome sequencing (WGS), stratified by CDS (green, 6.14 million biallelic SNPs) and non-CDS variants (orange, 549.64 million biallelic SNPs). The x axis shows six AC bins, from singletons (bin AC = 1, 44.8% of total variants) to common and low-frequency variants (AF ≥ 0.5%, 1.4% of total variants). For the plots, the center line represents the median, box limits are upper and lower quartiles, and whiskers are minimum and maximum values. Outliers are hidden for clarity. (C) PhyloP score density for ClinVar benign (N = 231,642), ClinVar pathogenic (N = 73,885), and gnomAD WGS variant positions with CADD ≥ 20 (N = 3,958,488).

**Fig. 2.. SNP-h² analyses of variants at constrained positions in human complex traits and diseases.**
(A) Heritability enrichment of common SNPs in the top percentiles of constraint scores in placental mammals (phyloP positions) and primates (phastCons elements). (B) Heritability enrichment as a function of the distance to a constrained base. (C) Heritability enrichment of constrained annotations in 11 blood and immune traits and nine brain diseases (light color) versus other types of traits (dark color). *P < 0.05 and **P < 0.05 after Bonferroni correction. (D) Heritability enrichment of constrained and functional annotations (left) and corresponding significance of the conditional effect while considered in a joint model with 106 annotations (right). GERP, genomic evolutionary rate profiling. (E) Heritability enrichment of constrained annotations intersected together and stratified by their genomic function. (F) Squared transancestry genetic correlation enrichment (left) with corresponding significance (right) for seven annotations with significant depletion of squared transancestry genetic correlations. H3K27ac, histone H3 acetylated at lysine 27. (G) Standardized squared effect sizes as a function of AF. Results are meta-analyzed across, 63 independent GWASs [(A), (B), (D), and (E)], 31 independent traits with GWASs available in European and Japanese populations [(F)], and 27 independent UK Biobank traits [(G)]. Dashed red lines represent a null enrichment of 1 [(A) to (E)] and a null squared transancestry genetic correlation (F). Error bars are 95% confidence intervals. Numerical results are reported in data S2 to S4, S6 to S8, and S11.

**Fig. 3.. Leveraging constraint to move from variation to function.**
(A and B) We report the cumulative distribution function (CDF) of PIP scores using functionally informed fine-mapping with different models of functional annotations. Distribution functions are split into subpanels according to whether the fine-mapped SNP overlaps high constraint scores in mammals (A) and primates (B). One-way Kolmogorov-Smirnov tests show that CDFs for PIP scores obtained from the baseline-LF model (blue) are lower (above) than the CDFs for PIP scores obtained from the baseline-LF+Zoonomia model (orange) with Bonferroni correction for N = 4 categories across panels (***P < 0.0001; NS is not significant). (C and D) Examples of constrained fine-mapped variants. We report GWAS P values (top) and corresponding PIP scores under different functionally informed fine-mapping models (bottom). The shapes of the data points correspond to constraint information. (E) Fine-mapped variants are not limited to the annotated genome, as exemplified by rs72782676 (red dot in the AF panel) in the GATA3 UNICORN locus. TFBS, transcription factor binding site; cCREs, candidate cis-regulatory regions. (F and G) Constraint is formally linked to function through MPRAs at the regional oligo (F) and base-pair (G) level for neutral, active, and allele-specific skewed effects. (H) For the *LDLR* promoter locus, the MPRA effect is strongly correlated with the phyloP score. Constrained (red) and unconstrained (orange) ClinVar pathogenic variants are plotted to highlight known deleterious positions. In (E) and (H), the dashed orange lines represent the 5% FDR threshold for constraint.

**Fig. 4.. Evolutionary constraint, PC genes, and human disease.**
(A) Scatterplot of PC gene clustering [uniform manifold approximation and projection (UMAP) and density-based spatial clustering of applications with noise (DBSCAN)]. The x and y axes are the UMAP coordinates. Each point is a PC gene (N = 19,386). Five clusters are labeled: (a) 56 genes whose CDS bases are in complex regions that align poorly; (b) 221 genes that are apparently human- or primate-specific; (c) 669 genes with good alignment and possible human-specific functions [e.g., five human leukocyte antigen (HLA) genes and 14 interferon-α genes]; (d) 15 genes, all highly constrained; and (e) all other 18,425 PC genes. Coloring shows fracCdsCons, where gray indicates least and red indicates most constrained with an anticlockwise gradient in mammalian constraint from the upper middle to lower right. (B and C) Gene constraint deciles versus external gene sets as “lollipop plots” Zoonomia fracCdsCons are shown in (B). A recapitulation of figure 3 from (3) with the LOEUF decile reversed and missing data shown is presented in (C). Each panel has six subgraphs for autosomal-recessive genes, ClinGen level 3 genes, essential genes from Hart, essential genes in mouse, olfactory receptor genes, and severe haploinsufficiency genes. The x axis is the constraint decile (0 is least, 9 is most constrained, 99 is missing). The y axis is the fraction of the PC genes in a gene set in each decile as represented by circles. (D) Gene heritability enrichment for SNPs linked to genes of each decile of fracCdsCons. The dashed red line represents a null enrichment of 1. Error bars are 95% confidence intervals. (E) Spearman’s correlation of the constraint fraction between the parts of PC genes. (F and G) Fraction of CDS constraint (fracCdsCons) versus fraction of promoter constraint (F) and fraction of distal enhancer constraint (G) (shrunk to values <0.3). For (F) and (G), each point is a PC gene, and *HOX* genes (purple) and *DEFB* genes (green) are highlighted. (H) Gene heritability enrichment for SNPs linked to genes of decile of constraint in different gene features, plotted as per (D).

**Fig. 5.. Cancer driver genes identified using NCCM rates.**
(A) Distribution of the rates of NCCM for medulloblastoma. (B) An example set of the candidate driver genes found either in pediatric (light blue) or adult (purple) samples. Age of diagnosis (years) of the patient is indicated together with the tumor subgroup. (C) The *ZFHX4* locus contains nine NCCMs drawn from eight patients.

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Update of

Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.
Sullivan PF, Meadows JRS, Gazal S, Phan BN, Li X, Genereux DP, Dong MX, Bianchi M, Andrews G, Sakthikumar S, Nordin J, Roy A, Christmas MJ, Marinescu VD, Wallerman O, Xue JR, Li Y, Yao S, Sun Q, Szatkiewicz J, Wen J, Huckins LM, Lawler AJ, Keough KC, Zheng Z, Zeng J, Wray NR, Johnson J, Chen J; Zoonomia Consortium; Paten B, Reilly SK, Hughes GM, Weng Z, Pollard KS, Pfenning AR, Forsberg-Nilsson K, Karlsson EK, Lindblad-Toh K. Sullivan PF, et al. bioRxiv [Preprint]. 2023 Mar 10:2023.03.10.531987. doi: 10.1101/2023.03.10.531987. bioRxiv. 2023. Update in: Science. 2023 Apr 28;380(6643):eabn2937. doi: 10.1126/science.abn2937 PMID: 36945512 Free PMC article. Updated. Preprint.

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

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