Biology subjects

Mazaheri, N.

Publications and source records attributed to Mazaheri, N..

3 recordsLinked to original sources

bioRxiv2024

Large-Scale Assessment of the Iranian population structure of Mitochondrial and Y-chromosome Haplogroups

The Iranian plateau, strategically positioned as a corridor for population diffusion across Eurasia, holds a pivotal role in elucidating the dynamics of human migrations originating from Africa around 60,000 years ago. Both prehistoric and historic movements of populations between Africa, Asia, and Europe may have been influenced by the unique geographical features of the Iranian plateau. Iran boasts ancient cultures and urban settlements predating some of the earliest civilizations, including the Neolithic revolution in neighboring Mesopotamia. Spanning from the Balkans and Egypt in the west to the Indus Valley in Pakistan and northern India in the southeast, the Iranian plateau encompasses a vast area characterized by incredible ethnocultural diversity. This region served as the origin for numerous mt-DNA/Y-DNA haplogroups that expanded to West Asia, Europe, Siberia, Central Asia, and South Asia. By examining both maternal and paternal haplogroups within the Iranian context, we aim to contribute to the broader narrative of human dispersals and elucidate the role those specific regions, such as the Iranian plateau, played in shaping the observed genetic diversity today. Due to the lack of comprehensive studies on mt-DNA /Y-DNA haplogroups in the Iranian population, our study sought to uncover the distribution of haplogroups among Iranian peoples using a large sample size. Our analysis focused on the frequency of ancestral haplogroups in Iran through the examination of large-scale whole-exome sequencing (WES) and SNP microarray data from 18,184 individuals. In our study, we observed 24 mt-DNA super haplogroups in the Iranian population, with the most common haplogroups belonging to West-Eurasian lineages U (20.73%), H (18.84%), J (12.10%), HV (9.22%), and T (8.98%), collectively comprising 69.70% of all Iranian samples. Notably, subclades J1 and U7 emerged as the two most frequent subclades, with frequencies of 11.24% and 7.30%, respectively. We also revealed the presence of 14 distinct Y-DNA haplogroups, with J, R, G, T, and Q emerging as the five predominant lineages. Notably, J2 (including J-L26) exhibited the highest frequency at 35.64%, followed by R1a at 14.68%. also, The detected mtDNA and Y-chromosome haplogroups were clustered into distinct groups that confirmed the heterogenicity of the Iranian population because of various factors including geographic or linguistic ethnic groups.

genetics↗

bioRxiv2021

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

genetics↗

bioRxiv2020

Biallelic mutation of CLRN2 causes non-syndromic hearing loss in humans

Deafness, the most frequent sensory deficit in humans, is extremely heterogenous with hundreds of genes probably involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 15.2 Mb locus on chromosome 4p15.32p15.1 containing a missense pathogenic variant in CLRN2 (c.494C>A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C>A mutation leads to two events: 1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and 2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

genetics↗