Publications by authors named "Vagheesh M Narasimhan"

8 Publications

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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Genet Med 2020 05 17;22(5):867-877. Epub 2020 Jan 17.

Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).

Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.

Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition.

Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
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http://dx.doi.org/10.1038/s41436-019-0743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200597PMC
May 2020

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

Cell 2019 10 5;179(3):729-735.e10. Epub 2019 Sep 5.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.
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http://dx.doi.org/10.1016/j.cell.2019.08.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800651PMC
October 2019

The formation of human populations in South and Central Asia.

Science 2019 09;365(6457)

Earth Institute, University College Dublin, Dublin 4, Ireland.

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages.
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http://dx.doi.org/10.1126/science.aat7487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822619PMC
September 2019

Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes.

Nat Commun 2017 08 21;8(1):303. Epub 2017 Aug 21.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' to 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.
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http://dx.doi.org/10.1038/s41467-017-00323-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566399PMC
August 2017

Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models.

Circ Res 2016 Dec 28;119(12):1313-1323. Epub 2016 Sep 28.

From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).

Rationale: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease, remain unresolved. In particular, it is not known whether all VSMCs proliferate and display plasticity or whether individual cells can switch to multiple phenotypes.

Objective: To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells.

Methods And Results: Using multicolor lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contributes to both alpha smooth muscle actin (aSma)-positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained the expression of VSMC markers and the upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease.

Conclusions: We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149073PMC
December 2016

Human Knockout Carriers: Dead, Diseased, Healthy, or Improved?

Trends Mol Med 2016 Apr 14;22(4):341-351. Epub 2016 Mar 14.

Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address:

Whole-genome and whole-exome sequence data from large numbers of individuals reveal that we all carry many variants predicted to inactivate genes (knockouts). This discovery raises questions about the phenotypic consequences of these knockouts and potentially allows us to study human gene function through the investigation of homozygous loss-of-function carriers. Here, we discuss strategies, recent results, and future prospects for large-scale human knockout studies. We examine their relevance to studying gene function, population genetics, and importantly, the implications for accurate clinical interpretations.
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http://dx.doi.org/10.1016/j.molmed.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826344PMC
April 2016

Health and population effects of rare gene knockouts in adult humans with related parents.

Science 2016 Apr 3;352(6284):474-7. Epub 2016 Mar 3.

Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.
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http://dx.doi.org/10.1126/science.aac8624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985238PMC
April 2016