TY - CHAP
T1 - Interrogating the Human Diplome
T2 - Computational Methods, Emerging Applications, and Challenges
AU - Chan, Agnes P.
AU - Choi, Yongwook
AU - Rangan, Aditya
AU - Zhang, Guangfa
AU - Podder, Avijit
AU - Berens, Michael
AU - Sharma, Sunil
AU - Pirrotte, Patrick
AU - Byron, Sara
AU - Duggan, Dave
AU - Schork, Nicholas J.
N1 - Funding Information:
The authors would like to acknowledge the following research support: NIH grants 1 U19 AG056169-01A1, U2C CA252973, UH2 AG064706, R01 EY028606, 5U01CA224153-03, 1U2CCA252973-01, and U19 AG023122 as well as a grant from the Animal Cancer Foundation (ACF; AOTHCON2440A003).
Publisher Copyright:
© 2023, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2023
Y1 - 2023
N2 - Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., “phase”) the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations—for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as “diplomics,” which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.
AB - Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., “phase”) the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations—for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as “diplomics,” which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.
KW - Cancer and DNA/RNA binding
KW - Epistasis
KW - Functional prediction
KW - Genetic variation
KW - Genomics
KW - Haplotyping
KW - Phasing
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U2 - 10.1007/978-1-0716-2819-5_1
DO - 10.1007/978-1-0716-2819-5_1
M3 - Chapter
C2 - 36335489
AN - SCOPUS:85141378660
T3 - Methods in Molecular Biology
SP - 1
EP - 30
BT - Methods in Molecular Biology
PB - Humana Press Inc.
ER -