Cell population‐based framework of genetic epidemiology in the single‐cell omics era

AbstractWe present a Minimal Event Distance Aneuploidy Lineage Tree (MEDALT) algorithm that infers the evolution history of a cell population based on single-cell copy number (SCCN) profiles, and a statistical routine named lineage speciation analysis (LSA), whichty facilitates discovery of fitness-associated alterations and genes from SCCN lineage trees. MEDALT appears more accurate than phylogenetics approaches in reconstructing copy number lineage. From data from 20 triple-negative breast cancer patients, our approaches effectively prioritize genes that are essential for breast cancer cell fitness and predict patient survival, including those implicating convergent evolution.The source code of our study is available at https://github.com/KChen-lab/MEDALT.

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TSHRMutations as a Cause of Congenital Hypothyroidism in Japan: A Population-Based Genetic Epidemiology Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-1767 ◽

2009 ◽

Vol 94 (4) ◽

pp. 1317-1323 ◽

Cited By ~ 54

Author(s):

Satoshi Narumi ◽

Koji Muroya ◽

Yoichiro Abe ◽

Masato Yasui ◽

Yumi Asakura ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Genetic Epidemiology ◽

Population Based ◽

Epidemiology Study

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The Western Australian Twin Register: A Population-Based Register of Adult and Child Multiples

Twin Research and Human Genetics ◽

10.1375/twin.9.6.712 ◽

2006 ◽

Vol 9 (6) ◽

pp. 712-717 ◽

Cited By ~ 2

Author(s):

Jessica D. Y. Lee ◽

Lyle J. Palmer

Keyword(s):

Medical Research ◽

Genetic Epidemiology ◽

Record Linkage ◽

Collaborative Research ◽

Data Linkage ◽

Population Based ◽

Multiple Births ◽

Efficient Management ◽

Twin Registry ◽

Western Australian

AbstractThe Western Australian Twin Register (WATR) was established in 1997 to study the health of all child multiples born in Western Australia (WA). The Register has until recently consisted of all multiples born in WA between 1980 and 1997. Using unique record linkage capacities available through the WA data linkage system, we have subsequently been able to identify all multiple births born in WA since 1974. New affiliations with the Australian Twin Registry and the WA Institute for Medical Research are further enabled by the use of the WA Genetic Epidemiology Resource — a high-end bioinformatics infrastructure that allows efficient management of health datasets and facilitates collaborative research capabilities. In addition to this infrastructure, funding provided by these institutions has allowed the extension of the WATR to include a greater number of WA multiples, including those born between 1974 and 1979, and from 1998 onwards. These resources are in the process of being enabled for national and international access.

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Of genes and twins

Psychological Medicine ◽

10.1017/s0033291703007980 ◽

2003 ◽

Vol 33 (5) ◽

pp. 763-768 ◽

Cited By ~ 1

Author(s):

KENNETH S. KENDLER

Keyword(s):

Genetic Epidemiology ◽

Large Population ◽

Genetic Research ◽

Population Based ◽

Gene Finding ◽

Adoption Studies ◽

Age Cohorts ◽

Psychological Medicine ◽

Quasi Experimental ◽

Twin Method

The two paradigms that now dominate the increasingly active field of psychiatric genetics – genetic epidemiology and gene-finding methods – are well illustrated by five papers in this issue of Psychological Medicine. Genetic epidemiology, which uses the classical ‘work-horse’ methods of family, twin and adoption studies, infers the action of genetic and environmental risk factors by observing the pattern of resemblance of traits or disorders in various classes of relatives. Methods that are utilized in genetic epidemiology can range from great simplicity, such as the odds ratio of a disorder in first-degree relatives of affected versus matched control probands, to substantial complexity, as seen in some advanced multivariate twin-family models (Truett et al. 1994). Of the quasi-experimental methods available to psychiatric geneticists that can tease apart the effects of genetic and shared-environmental factors (nature versus nurture), the twin method has become increasingly popular. This is probably due to the increasing availability of large population-based or volunteer twin registries (see the Oct 2002 issue of Twin Research on ‘Twin Registers as a Global Resource for Genetic Research’) that can be utilized to study psychiatric and drug abuse disorders. By contrast, due to changing social circumstances in most Western countries, adoption, even in the Scandinavian countries where most of the classic studies have been done, is becoming so rare that new adoption studies with younger age cohorts are hardly feasible. By contrast, gene-finding methods, which utilized variants of two different methods of linkage or association, have the goal of determining, on the human genome, the location and potential identity of susceptibility genes.

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Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination

mBio ◽

10.1128/mbio.00942-13 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 33

Author(s):

Xiaorong Wang ◽

Yu Kang ◽

Chunxiong Luo ◽

Tong Zhao ◽

Lin Liu ◽

...

Keyword(s):

Growth Rate ◽

Single Cell ◽

Task Allocation ◽

Bacterial Population ◽

Population Based ◽

Phenotypic Heterogeneity ◽

Single Cell Level ◽

Bacterial Survival ◽

Cell Level ◽

Resistant Cells

ABSTRACT Heteroresistance refers to phenotypic heterogeneity of microbial clonal populations under antibiotic stress, and it has been thought to be an allocation of a subset of “resistant” cells for surviving in higher concentrations of antibiotic. The assumption fits the so-called bet-hedging strategy, where a bacterial population “hedges” its “bet” on different phenotypes to be selected by unpredicted environment stresses. To test this hypothesis, we constructed a heteroresistance model by introducing a bla CTX-M-14 gene (coding for a cephalosporin hydrolase) into a sensitive Escherichia coli strain. We confirmed heteroresistance in this clone and that a subset of the cells expressed more hydrolase and formed more colonies in the presence of ceftriaxone (exhibited stronger “resistance”). However, subsequent single-cell-level investigation by using a microfluidic device showed that a subset of cells with a distinguishable phenotype of slowed growth and intensified hydrolase expression emerged, and they were not positively selected but increased their proportion in the population with ascending antibiotic concentrations. Therefore, heteroresistance—the gradually decreased colony-forming capability in the presence of antibiotic—was a result of a decreased growth rate rather than of selection for resistant cells. Using a mock strain without the resistance gene, we further demonstrated the existence of two nested growth-centric feedback loops that control the expression of the hydrolase and maximize population growth in various antibiotic concentrations. In conclusion, phenotypic heterogeneity is a population-based strategy beneficial for bacterial survival and propagation through task allocation and interphenotypic collaboration, and the growth rate provides a critical control for the expression of stress-related genes and an essential mechanism in responding to environmental stresses. IMPORTANCE Heteroresistance is essentially phenotypic heterogeneity, where a population-based strategy is thought to be at work, being assumed to be variable cell-to-cell resistance to be selected under antibiotic stress. Exact mechanisms of heteroresistance and its roles in adaptation to antibiotic stress have yet to be fully understood at the molecular and single-cell levels. In our study, we have not been able to detect any apparent subset of “resistant” cells selected by antibiotics; on the contrary, cell populations differentiate into phenotypic subsets with variable growth statuses and hydrolase expression. The growth rate appears to be sensitive to stress intensity and plays a key role in controlling hydrolase expression at both the bulk population and single-cell levels. We have shown here, for the first time, that phenotypic heterogeneity can be beneficial to a growing bacterial population through task allocation and interphenotypic collaboration other than partitioning cells into different categories of selective advantage.

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Resolution of DNA damage at the single-cell level shows largely different actions of X-rays and bleomycin.

Journal of Histochemistry & Cytochemistry ◽

10.1177/43.2.7529787 ◽

1995 ◽

Vol 43 (2) ◽

pp. 229-235 ◽

Cited By ~ 6

Author(s):

M I Affentranger ◽

W Burkart

Keyword(s):

Single Cell ◽

Cell Population ◽

Large Cell ◽

Dna Strand Breaks ◽

Single Cell Level ◽

X Rays ◽

Cell Level ◽

Strand Breaks ◽

Two Agents ◽

Dna Strand

Both X-rays and the radiomimetic agent bleomycin (BLM) induce DNA strand breaks, predominantly via reactive radicals. To compare the induction of breaks with the two agents in Chinese hamster (CHO-K1) cells, two different alkaline unwinding methods, a 3H tracer-based analysis of large cell populations and an optical adaption allowing measurement of single cells, were applied. Radiation and BLM show qualitatively similar dose responses when the average number of DNA strand breaks is measured in a large cell population. However, the breakage pattern at the single-cell level indicates large discrepancies between the actions of the two agents. Irradiated cells show a uniform distribution of DNA strand breaks over the cell population. Effects of treatment with 30 micrograms x ml-1 BLM for 2 hr vary from practically zero in some cells to high levels of DNA strand breakage in others. Unlike the repair of radiation-induced DNA breaks, the repair efficiency of BLM-induced DNA strand breaks, as measured at the single-cell level, varies strongly among cells of the same population. Such heterogeneity at the cellular level potentially reduces BLM's usefulness for tumor therapy because the appearance of BLM-resistant subpopulations may critically impair treatment outcome.

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