Biology subjects

Kong, A.

Publications and source records attributed to Kong, A..

4 recordsLinked to original sources

bioRxiv2017

Recurrence of de novo mutations in families

De novo mutations (DNMs) cause a large fraction of severe rare diseases of childhood. DNMs that occur in early embryos may result in mosaicism of both somatic and germ cells. Such early mutations may be transmitted to more than one offspring and cause recurrence of serious disease. We scanned 1,007 sibling pairs from 251 families and identified 885 DNMs shared by siblings (ssDNMs) at 451 genomic sites. We estimated the probability of DNM recurrence based on presence in the blood of the parent, sharing by other siblings, parent-of-origin, mutation type, and genomic position. We detected 52.1% of ssDNMs in the parental blood. The probability of a DNM being shared goes down by 2.28% per year for paternal DNMs and 1.82% for maternal DNMs. Shared paternal DNMs are more likely to be T>C mutations than maternal ones, but less likely to be C>T mutations. Depending on DNM properties, the probability of recurrence in a younger sibling ranges from 0.013% to 29.6%. We have launched an online DNM recurrence probability calculator, to use in genetic counselling in cases of rare genetic diseases.

genomics↗

bioRxiv2017

Estimating heritability without environmental bias

Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is of importance to the nature-versus-nurture debate. However, existing estimates of heritability could be biased by environmental effects. Here we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR removes environmental bias by exploiting variation in relatedness due to random segregation. We use a sample of 54,888 Icelanders with both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, S.E. 4.4%) and educational attainment (17.0%, S.E. 9.4%). Our results suggest that some other estimates of heritability could be inflated by environmental effects.

genetics↗

bioRxiv2017

The nature of nurture: effects of parental genotypes

Sequence variants in the parental genomes that are not transmitted to a child/proband are often ignored in genetic studies. Here we show that non-transmitted alleles can impact a child through their effects on the parents and other relatives, a phenomenon we call genetic nurture. Using results from a meta-analysis of educational attainment, the polygenic score computed for the non-transmitted alleles of 21,637 probands with at least one parent genotyped has an estimated effect on the educational attainment of the proband that is 29.9% (P = 1.6x10-14) of that of the transmitted polygenic score. Genetic nurturing effects of this polygenic score extend to other traits. Paternal and maternal polygenic scores have similar effects on educational attainment, but mothers contribute more than fathers to nutrition/heath related traits.\n\nOne Sentence SummaryNurture has a genetic component, i.e. alleles in the parents affect the parents phenotypes and through that influence the outcomes of the child.

genetics↗

bioRxiv2017

Type 2 diabetes promotes cell centrosome amplification and the role of AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ

Type2 diabetes is associated with oxidative stress which can cause cell centrosome amplification. The study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. We found that centrosome amplification was increased in the peripheral blood mononuclear cells (PBMC) from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3{sigma}. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3{sigma} was the molecular pathway underlying the centrosome amplification induced by high glucose, insulin and palmitic acid. Moreover, the increases in AKT activation and ROS production as well as expression, binding and centrosome distribution of ROCK1 and 14-3-3{sigma} were confirmed in the PBMC from the patients with type 2 diabetes. In conclusion, our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3{sigma} is the underlying molecular mechanism.

cell biology↗