Human Molecular Genetics, 2022, Vol.

31, R1, R1–R3

https://doi.org/10.1093/hmg/ddac219
Editorial

Editorial

Human Molecular Genetics Review Issue 2022

Recent remarkable advances in high-throughput genotyping and without substantial programming skills, making this area of
next-generation DNA-sequencing technologies have generated genome annotation more readily available to biologists and
massive human genome sequencing datasets, fueling genome- geneticists. Castaldi et al. provide an overview of the latest
wide association studies (1) and whole-genome/exome sequenc- approaches for genome-wide mapping of splicing quantitative
ing studies (2,3), which have greatly informed our understanding trait loci (sQTL) (13). They present illustrative examples on how to
of the rare and common genetic contributions to disease (4). Most use long-read sequencing to characterize sQTL effects on protein
of these variants lie outside protein coding regions in presumed isoforms and the linkage of RNA isoforms to protein-level function
non-coding, regulatory regions (5,6). Thus, the incomplete regula- impact by human disease-associated variants (13). Wang et al.
tory annotation of the genome, whose effects are developmental review the latest work on noncoding RNA (noRNAs) and their
stage and cell-type specific, complicates the identification of functional roles using Alzheimer’s disease (ad) as example (14). In
functional noncoding genetic variants and their causal associ- particular, they discuss how to identify biomarkers and therapeu-
ation with disease (6,7). The challenge is further amplified by tic targets from ncRNA signatures, interactions between ncRNAs
linkage disequilibrium, which hinders the identification of the and mRNA, and ncRNA-regulated pathways in ad by leveraging
true causal variants at each locus in genome-wide association data from multi-omic studies. Xu et al. review recent advances
studies (GWAS) (8,9). This has fueled the recent development of building gene regulatory elements to characterize gene expres-
both computational methods (10) and highly parallelized exper- sion impacted by non-coding variation (15). The authors summa-
imental assays (4) that have opened new avenues to efficiently rize strengths and shortcomings of current functional assays and
identify functional noncoding variation, therapeutic targets and evolutionary analyses, and highlight future directions by leverag-
diagnostic tools. ing new techniques to create new gene regulatory maps of ever-
In this special issue, we are very pleased to present a curated increasing resolution and comprehensiveness (15). Bykova et al.
collection of timely, authoritative reviews of this rapidly moving present an overview of multiple molecular quantitative trait locus
field, which we expect will be of general interest to the genomic phenotypes (xQTL) to characterize the genetic architecture of
medicine community. Interrogation of the role and mechanisms noncoding loci impacting the human transcriptome, epigenome,
of noncoding variants has been rapidly introduced into different proteome and metabolome (16). In particular, they discuss the
subfields of genome medicine, including, evolution, discovery recent development of xQTL and highlight multimodal analysis
of disease-associated loci and genes, understanding of disease of xQTL and multi-omics data for identification of risk genes and
mechanisms, identifying diagnostic tools and drug targets. drug targets from noncoding genetic loci. They further discuss
In this special issue, we compile an exciting group of com- challenges and future research directions, including Artificial
prehensive reviews from diverse perspectives on topics ranging Intelligence and machine learning technologies for annotation of
from functional non-coding variant prediction and annotation, to non-coding variants in human complex diseases (16).
discovery and validation of disease-associated loci and genes, to Because current computational methods have many pitfalls
document the innovation, recent progress, and potential biomedi- with regards to non-coding variant prioritization, including
cal impact of computational and experimental approaches in this limited predictive power and lack of agreement among most
area. We start with computational approaches and resources, methods, the application of high-throughput experimental assays
followed by functional assays. Kuksa et al. describe the latest play an essential role in current attempts to understand the
scalable tools, databases and functional genomic resources functional consequences of noncoding variation. Jones et al.
to interpret non-coding variant findings from whole-genome review high throughput CRISPRi and CRISPRa technologies in
sequencing data (11). They review both experimental data and identifying 3D genome regulation using neuropsychiatric diseases
in silico annotation (such as machine learning-based predictive as examples (17). They discuss existing challenges of interpreting
models) for variants scoring and prioritization. Schipper and the biological function of the non-coding genome and approaches
Posthuma comprehensively summarize recent computational to prioritizing disease-associated variants from a 3D epigenome
tools and methods to generate in silico hypothesis related to non- perspective. Mew et al. summarize the functional annotation
coding GWAS variant function in human diseases and to prioritize of human variants, mostly coding, using invertebrate in vivo
targets for follow-up studies (12). Many of the tools they and models (such as Drsophila and Caenorhabditis elegans). They
colleagues have developed are readily accessible to researchers review various available resources of f ly and worm models and

Received: August 30, 2022. Revised: August 30, 2022. Accepted: August 30, 2022
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
R2 | Human Molecular Genetics, 2022, Vol. 31, No. R1

illustrate several examples of functional annotation of non- 3. Taliun, D., Harris, D.N., Kessler, M.D., Carlson, J., Szpiech, Z.A.,
coding variants from GWAS across a range of neurodevelopmental Torres, R., Taliun, S.A.G., Corvelo, A., Gogarten, S.M., Kang, H.M.
and neurodegenerative disorders (18). Leung et al. encapsulate et al. (2021) Sequencing of 53,831 diverse genomes from the nhlbi
recent functional genomic assays and tools to characterize topmed program. Nature, 590, 290–299.
genome-wide enhancer-promoter interactions impacted by 4. Cooper, Y.A., Teyssier, N., Drager, N.M., Guo, Q., Davis, J.E., Sattler,
noncoding variations (19). They highlight recent advances in high- S.M., Yang, Z., Patel, A., Wu, S., Kosuri, S. et al. (2022) Functional
throughput methods to quantitatively characterize enhancer- regulatory variants implicate distinct transcriptional networks
promoter interactions, including chromosome conformation in dementia. Science, 377, eabi8654.
capture assays (e.g. Hi-C), ectopic reporter experiments (e.g. 5. Maurano, M.T., Humbert, R., Rynes, E., Thurman, R.E., Hau-
STARR-seq) and endogenous perturbation (e.g. CRISPRi) (19). gen, E., Wang, H., Reynolds, A.P., Sandstrom, R., Qu, H.,
Cooper et al. survey highly parallelized experimental assays Brody, J. et al. (2012) Systematic localization of common
to characterize human noncoding genetic variation at large- disease-associated variation in regulatory DNA. Science, 337,
scale, including massively parallel reporter assays (MPRA) and 1190–1195.
CRISPR-based pooled screens (20). Owing to potential limitations 6. Broekema, R.V., Bakker, O.B. and Jonkers, I.H. (2020) A practi-
of each assay, they highlight that multiplexed assays of variant cal view of fine-mapping and gene prioritization in the post-
effects play a crucial role in the functional and experimental genome-wide association era. Open Biol., 10, 190221.
annotation of noncoding disease variants, identifying the 7. Tewhey, R., Kotliar, D., Park, D.S., Liu, B., Winnicki, S., Reilly,
underlying functional consequences of disease-associated loci S.K., Andersen, K.G., Mikkelsen, T.S., Lander, E.S., Schaffner,
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complex diseases (20), in particular for Alzheimer’s disease expression-modulating variants using a multiplexed reporter
and related dementia by lack of effective disease-modifying assay. Cell, 165, 1519–1529.
treatments. 8. Schaid, D.J., Chen, W. and Larson, N.B. (2018) From genome-wide
Overall, the field is moving rapidly and these reviews high- associations to candidate causal variants by statistical fine-
light the great promise heralded by recent work annotating and mapping. Nat. Rev. Genet., 19, 491–504.
identifying functional non-coding variants across many basic and 9. Uffelmann, E., Huang, Q., Munung, N.S., de Vries, J., Okada,
clinical contexts. As functional tissue and stage-specific data pro- Y., Martin, A.R., Martin, H.C., Lappalainen, T. and Posthuma,
liferate, we anticipate that these data will help inform improved D. (2018) Genome-wide association studies. Nat. Rev. Methods
computational tools, likely rooted in machine learning, that can Primers, 1, 59.
further accelerate discovery. Because most disease-related vari- 10. Cheng, F., Zhao, J., Wang, Y., Lu, W., Liu, Z., Zhou, Y., Martin,
ation lies in non-coding regions, there remains a critical need W.R., Wang, R., Huang, J., Hao, T. et al. (2021) Comprehensive
to not only apply current approaches more broadly across dis- characterization of protein-protein interactions perturbed by
eases and tissues, but to further develop new experimental and disease mutations. Nat. Genet., 53, 342–353.
computational tools for genome medicine approaches to reach 11. Kuksa, P.P., Greenfest-Allen, E., Cifello, J., Ionita, M., Wang, H.,
its full potential. We are grateful to all of the authors of the Issen, H., Cheng, P.L., Lee, W.P., Wang, L.S. and Leung, Y.Y.
reviews in this timely overview of recent studies documenting (2022) Scalable approaches for functional analyses of whole-
the transformative impact of decoding the noncoding genome in genome sequencing non-coding variants. Hum. Mol. Genet., 31,
different subfields of genomic medicine. R62–R72.
12. Schipper, M. and Posthuma, D. (2022) Demystifying non-coding
gwas variants: An overview of computational tools and meth-
Acknowledgements ods. Hum. Mol. Genet., 31, R73–R83.
This work was supported by the National Health of Insti- 13. Castaldi, P.J., Abood, A., Farber, C.R. and Sheynkman, G.M. (2022)
tutes under Award Number U01AG073323, R01AG066707 and Bridging the splicing gap in human genetics with long-read rna
R01AG076448, and R56AG074001 to F.C., and R01MH100027, sequencing: Finding the protein isoform drivers of disease. Hum.
UG3NS104095, U01MH116489, U54NS123746, the Rainwater Mol. Genet., 31, R123–R136.
Charitable Foundation and the Simons Foundation to D.H.G. 14. Wang, E., Duarte, M.L., Rothman, L.E., Cai, D. and Zhang, B.
(2022) Non-coding rnas and alzheimer’s disease: Perspectives
from omics studies. Hum. Mol. Genet., 31, R54–R61.
15. Xu, J., Pratt, H.E., Moore, J.E., Gerstein, M.B. and Weng, Z. (2022)
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