Konstantin Popadin
My topic is slightly-deleterious variants. Even though most of these mutations individually have a small effect, their cumulative burden could substantially reduce the fitness of a cell, an individual, a population.
During my PostDoc in Harvard Medical School I worked on Deleterious In Late Life (DILL) variants and human aging. We discovered, that mitochondrial nucleotide repeats (which are DILL) increases the rate of origin of mitochondrial somatic deletions and thus accelerate age-related phenotypes such as neurodegeneration and sarcopenia and human aging per se (Guo X*, Popadin K* et al. 2010 TIG; Popadin et al. 2014 Aging Cell). The disruption of the nucleotide repeats cancels their deleterious effect, decreasing the rate of somatic mitochondrial deletions and making human aging more healthy. This mechanism particularly can explain an excess of centenarians in Japanese Haplogroup D4A with disrupted common repeat in mitochondrial genome (Popadin et al. 2008 Nature Precedings; Mikhailova et al. 2019 BioRxiv). We propose, that the beneficial properties of some mitochondrial haplogroups (such as D4a) can be used in mitochondrial donation technology.
During my PostDoc in Switzerland I discovered that regulatory variants (cis-eQTLs) affect predominantly evolutionary young, less functionally constrained genes of our genome (Popadin et al. 2013 AJHG; Popadin et al. 2014 AJHG). The integral deleterious effect of all these slightly-deleterious variants (integral transcriptome perturbation) can shape human embryonic selection. In case of Down Syndrome individuals this effect is the most pronounced: only a fetuses with initially low burden of slightly-deleterious variants may tolerate the extra chromosome and escape embryonic lethality (“The Genetic Handicap hypothesis”, Popadin et al. 2018 GenRes). The Genetic Handicap approach, when used in experiments with model organisms, can help to assign deleterious effect of hundreds slightly-deleterious variants at once and thus to reconstruct effectively fitness from genomic data.
During my PhD at Lomonosov Moscow State University I found out that genome-wide burden of slightly–deleterious variants (nonsynonymous, radical) is higher in species with low effective population size (Popadin et. al. 2007 PNAS; Nikolaev et. al. 2007 PNAS; Popadin et al. 2013 MolBiolEvol). This burden of slightly-deleterious variants provides a genetic component of extinction of large-bodied mammals (Polishchuk*, Popadin* et al. 2015 OIKOS). On the basis of our results we demonstrate how important to take into account not only ecological but also genetic data (which are proxy for short- and long-term effective population size) when assign a conservation status of a species.
I maintain all three scales of my research line (cellular, organismal, population) which synergistically interact with each other allowing me to do universal observations. Recently, for example, comparing mitochondrial mutational spectra between different cells in our body and different organisms of mammalian species we found out that ratio of transitions T>C/G>A positively correlate with cellular and organismal longevity (Mikhaylova et al. 2019 BioRhiv). We propose, that this universal functional mitochondrial marker can be used to investigate cell properties in complex heterogeneous samples.
During my PostDoc in Harvard Medical School I worked on Deleterious In Late Life (DILL) variants and human aging. We discovered, that mitochondrial nucleotide repeats (which are DILL) increases the rate of origin of mitochondrial somatic deletions and thus accelerate age-related phenotypes such as neurodegeneration and sarcopenia and human aging per se (Guo X*, Popadin K* et al. 2010 TIG; Popadin et al. 2014 Aging Cell). The disruption of the nucleotide repeats cancels their deleterious effect, decreasing the rate of somatic mitochondrial deletions and making human aging more healthy. This mechanism particularly can explain an excess of centenarians in Japanese Haplogroup D4A with disrupted common repeat in mitochondrial genome (Popadin et al. 2008 Nature Precedings; Mikhailova et al. 2019 BioRxiv). We propose, that the beneficial properties of some mitochondrial haplogroups (such as D4a) can be used in mitochondrial donation technology.
During my PostDoc in Switzerland I discovered that regulatory variants (cis-eQTLs) affect predominantly evolutionary young, less functionally constrained genes of our genome (Popadin et al. 2013 AJHG; Popadin et al. 2014 AJHG). The integral deleterious effect of all these slightly-deleterious variants (integral transcriptome perturbation) can shape human embryonic selection. In case of Down Syndrome individuals this effect is the most pronounced: only a fetuses with initially low burden of slightly-deleterious variants may tolerate the extra chromosome and escape embryonic lethality (“The Genetic Handicap hypothesis”, Popadin et al. 2018 GenRes). The Genetic Handicap approach, when used in experiments with model organisms, can help to assign deleterious effect of hundreds slightly-deleterious variants at once and thus to reconstruct effectively fitness from genomic data.
During my PhD at Lomonosov Moscow State University I found out that genome-wide burden of slightly–deleterious variants (nonsynonymous, radical) is higher in species with low effective population size (Popadin et. al. 2007 PNAS; Nikolaev et. al. 2007 PNAS; Popadin et al. 2013 MolBiolEvol). This burden of slightly-deleterious variants provides a genetic component of extinction of large-bodied mammals (Polishchuk*, Popadin* et al. 2015 OIKOS). On the basis of our results we demonstrate how important to take into account not only ecological but also genetic data (which are proxy for short- and long-term effective population size) when assign a conservation status of a species.
I maintain all three scales of my research line (cellular, organismal, population) which synergistically interact with each other allowing me to do universal observations. Recently, for example, comparing mitochondrial mutational spectra between different cells in our body and different organisms of mammalian species we found out that ratio of transitions T>C/G>A positively correlate with cellular and organismal longevity (Mikhaylova et al. 2019 BioRhiv). We propose, that this universal functional mitochondrial marker can be used to investigate cell properties in complex heterogeneous samples.
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efficiency of purifying selection by Konstantin Popadin
mitochondrial genome in aging and cancer by Konstantin Popadin
mitochondrial genomes of postmitotic cells, which accumulate large-scale somatic mitochondrial deletions with time,
leading to neurodegeneration, muscular dystrophy and aging. Slowing down the rate of origin of these somatic deletions
may benefit human lifespan and healthy aging. The main factors determining breakpoints of somatic mitochondrial
deletions are direct nucleotide repeats, which might be considered as Deleterious In Late Life (DILL) alleles.
Correspondingly, the decreased amount of these DILL alleles might lead to low production of somatic deletions and
increased lifespan. Intriguingly, in the Japanese D4a haplogroup, which is famous for an excess of centenarians and
supercentenarians, we found that the longest direct repeat (“common repeat”) in the human mitochondrial genome has
been disrupted by a point synonymous mutation. Thus we hypothesize that the disruption of the common repeat annuls
common deletion (which is the most frequent among all somatic deletions) and at least partially may contribute to the
extreme longevity of the D4a Japanese haplogroup. Here, to better understand the mitochondrial components of
longevity and potential causative links between repeats, deletions and longevity we discuss molecular, population and
evolutionary factors affecting dynamics of mitochondrial direct repeats.
transcriptome variation and fitness by Konstantin Popadin
mitochondrial genomes of postmitotic cells, which accumulate large-scale somatic mitochondrial deletions with time,
leading to neurodegeneration, muscular dystrophy and aging. Slowing down the rate of origin of these somatic deletions
may benefit human lifespan and healthy aging. The main factors determining breakpoints of somatic mitochondrial
deletions are direct nucleotide repeats, which might be considered as Deleterious In Late Life (DILL) alleles.
Correspondingly, the decreased amount of these DILL alleles might lead to low production of somatic deletions and
increased lifespan. Intriguingly, in the Japanese D4a haplogroup, which is famous for an excess of centenarians and
supercentenarians, we found that the longest direct repeat (“common repeat”) in the human mitochondrial genome has
been disrupted by a point synonymous mutation. Thus we hypothesize that the disruption of the common repeat annuls
common deletion (which is the most frequent among all somatic deletions) and at least partially may contribute to the
extreme longevity of the D4a Japanese haplogroup. Here, to better understand the mitochondrial components of
longevity and potential causative links between repeats, deletions and longevity we discuss molecular, population and
evolutionary factors affecting dynamics of mitochondrial direct repeats.