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The microcephalin ancestral allele in a Neanderthal individual.

ABSTRACT: BACKGROUND: The high frequency (around 0.70 worldwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans >1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the first PCR amplification and high-throughput sequencing of nuclear DNA at the microcephalin (MCPH1) locus from Neanderthal individual from Mezzena Rockshelter (Monti Lessini, Italy). We show that a well-preserved Neanderthal fossil dated at approximately 50,000 years B.P., was homozygous for the ancestral, non-D, allele. The high yield of Neanderthal mtDNA sequences of the studied specimen, the pattern of nucleotide misincorporation among sequences consistent with post-mortem DNA damage and an accurate control of the MCPH1 alleles in all personnel that manipulated the sample, make it extremely unlikely that this result might reflect modern DNA contamination. CONCLUSIONS/SIGNIFICANCE: The MCPH1 genotype of the Monti Lessini (MLS) Neanderthal does not prove that there was no interbreeding between anatomically archaic and modern humans in Europe, but certainly shows that speculations on a possible Neanderthal origin of what is now the most common MCPH1 haplogroup are not supported by empirical evidence from ancient DNA.

SUBMITTER: Lari M

PROVIDER: S-EPMC2871044 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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The microcephalin ancestral allele in a Neanderthal individual.

Lari Martina M Rizzi Ermanno E Milani Lucio L Corti Giorgio G Balsamo Carlotta C Vai Stefania S Catalano Giulio G Pilli Elena E Longo Laura L Condemi Silvana S Giunti Paolo P Hänni Catherine C De Bellis Gianluca G Orlando Ludovic L Barbujani Guido G Caramelli David D

PloS one 20100514 5

<h4>Background</h4>The high frequency (around 0.70 worldwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans >1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogrou ...[more]

PMID: 20498832

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Project description:Mitochondria are arising as critical modulators of antiviral tolerance by releasing mtDNA/mtRNA fragments to cytoplasm upon infection, activating virus sensors and type-I interferon response. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here, we investigated mitochondrial recessive ataxia syndrome (MIRAS), caused by a common European founder mutation in DNA polymerase gamma (POLG1). The patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages-of-onset and symptoms, indicating unknown modifying factors contributing to disease manifestation. We report that the mitochondrial DNA (mtDNA) replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV, SARS-CoV-2) and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release to cytoplasm and slow interferon response in MIRAS allow an early replicative advantage for viruses, leading to augmented pro-inflammatory response, subacute loss of GABAergic neurons, liver inflammation and necrosis. A population databank of ~300,000 Finns demonstrates enrichment of immunodeficient traits in p.W748S carriers. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications to mitochondrial disease spectrum, including epilepsy, ataxia, and parkinsonism. In this metabolomic dataset: To investigate the in vivo response of MIRAS to viral infection, we generated a MIRAS-knock-in mouse model and subjected the mice to TBEV infection. These animals carry a homozygous knock-in mutation and the accompanying polymorphic variant homologous to the human ancestral MIRAS allele (p.W726S+E1121G in mice and p.W748S+E1143G in humans). We performed metabolomic analyses on the mouse brain (cerebral cortex) isolated from the control (wildtype) and MIRAS mice at 4 days post TBEV infection (n=5 mice per condition).

Dataset Information

The microcephalin ancestral allele in a Neanderthal individual.

Publications

The microcephalin ancestral allele in a Neanderthal individual.

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