Biology subjects

Jizi, K.

Publications and source records attributed to Jizi, K..

3 recordsLinked to original sources

bioRxiv2026

Dose-dependent myelin g-ratio alterations in the white matter of 16p11.2 copy number variations

Copy number variations (CNVs) at the 16p11.2 locus are major genetic risk factors for neurodevelopmental conditions and drive reciprocal alterations in cerebral white matter structure and connectivity. However, whether these alterations reflect differences in the axonal or myelin compartments remains unresolved with conventional diffusion MRI. We combined diffusion MRI with magnetization transfer saturation mapping across two ComBat-harmonized cohorts comprising 80 controls, 26 16p11.2 deletion carriers, and 13 duplication carriers. We quantified axonal volume, myelin volume, and aggregate g-ratio of white matter tracts forming the structural connectome. Metrics were evaluated using normative modeling across tract length, resting-state functional networks, and cortical nodes. We additionally examined 29 individuals carrying other neurodevelopmental CNVs. 16p11.2 gene dosage was associated with regional reciprocal differences in tract axonal volume, with greater volume in deletion carriers and lower volume in duplication carriers. In contrast, myelin volume did not differ significantly from controls. This mismatch resulted in pervasive aggregate g-ratio alterations, with higher g-ratios (relatively thinner myelin sheaths) in deletion carriers and lower g-ratios (relatively thicker sheaths) in duplication carriers. Regional g-ratio alterations also extended to other neurodevelopmental CNVs. These findings resolve some of the biological ambiguity underlying white matter alterations in 16p11.2 CNV carriers, implicating the axonal compartment while revealing comparatively stable myelin volume. The disrupted axon-myelin scaling results in connectome-wide g-ratio alterations and may represent a shared microstructural hallmark of genetic neurodevelopmental risk.

neuroscience↗

bioRxiv2023

Using rare genetic mutations to revisit structural brain asymmetry

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

neuroscience↗

bioRxiv2020

Estimating the effect-size of gene dosage on cognitive ability across the coding genome

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

genetics↗