Profiling genetically driven alternative splicing across the Indonesian archipelago

Journal article


Ibeh, Neke, Kusuma, Pradiptajati, Crenna Darusallam, Chelzie, Malik, Safarina G., Sudoyo, Herawati, McCarthy, Davis J. and Gallego Romero, Irene. (2024). Profiling genetically driven alternative splicing across the Indonesian archipelago. American Journal of Human Genetics. 111(11), pp. 2458-2477. https://doi.org/10.1016/j.ajhg.2024.09.004
AuthorsIbeh, Neke, Kusuma, Pradiptajati, Crenna Darusallam, Chelzie, Malik, Safarina G., Sudoyo, Herawati, McCarthy, Davis J. and Gallego Romero, Irene
Abstract

One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.

Year2024
JournalAmerican Journal of Human Genetics
Journal citation111 (11), pp. 2458-2477
PublisherCell Press
ISSN0002-9297
Digital Object Identifier (DOI)https://doi.org/10.1016/j.ajhg.2024.09.004
PubMed ID39383868
Scopus EID2-s2.0-85207357067
PubMed Central IDPMC11568790
Open accessPublished as ‘gold’ (paid) open access
Page range2458-2477
FunderNational Health and Medical Research Council (NHMRC)
Australian Research Council (ARC)
Wellcome Trust
European Union
European Regional Development Fund (FEDER)
Operational Infrastructure Support (OIS) Program, Victorian Government
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online07 Nov 2024
Publication process dates
Accepted12 Sep 2024
Deposited03 Apr 2025
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDGNT1195595
GNT1112681
GNT1162829
DP200101552
GNT2020501
222992/Z/21/Z
810645
MOBEC008
Additional information

© 2024 The Author(s). Published by Elsevier Inc. on behalf of American Society of Human Genetics.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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