What’s new in research at Mass General? Here’s a snapshot of studies recently published in top-tier scientific journals:

NEW INSIGHTS INTO HOW GENETICS INFLUENCE MIGRAINES

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families
Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Häppölä P [et al.], Palotie A
Published in Neuron on May 3, 2018

Migraine tends to run in families, but it’s not clear if this clustering in families is due to rare, highly penetrant variants in individual genes or common ones with small effect sizes spread across many genes. Our team built a polygenic risk score using data from a migraine genome-wide association study, and used it to study the impacts of common and rare variation in a large cohort of families. We found a higher risk score in familial migraine cases, suggesting that common variants play a significant role in aggregation of migraine in families.

(Summary submitted by Aarno Palotie, PhD, MD, and Padhraig James Gormley, PhD, of the Department of Psychiatry)

COMPREHENSIVE VIEW OF FINLAND’S EVOLUTIONARY HISTORY

Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland
Martin AR, Karczewski KJ, Kerminen S, Kurki MI, Sarin AP, Artomov M [et al.], Daly MJ
Published in American Journal of Human Genetics on May 3, 2018

Finland is a great place to infer population history and query disease genetics because it has a well-characterized history as a small founder population, unified medical records, and biobank-scale genetic data. Our international study assembled a comprehensive view of its evolutionary history by measuring segmental DNA sharing among pairs of Finns and individuals from neighboring countries that were inherited from common ancestors. We coupled this information with birth records to infer recent historical population dynamics, including population size changes, migration rates, and admixture events over time. We also traced the rise and spread of rare variants known to confer Finnish-specific disease risk that increased in frequency during the population bottleneck.

(Summary submitted by Alicia Martin, PhD, of the Department of Medicine)

DIAGNOSIS OF BREAST CANCER DETECTED BETWEEN SCREENINGS

Breast Cancer With a Poor Prognosis Diagnosed After Screening Mammography With Negative Results
McCarthy AM, Barlow WE, Conant EF, Haas JS, Li CI, Sprague BL, Armstrong K
Published in JAMA Oncology on May 3, 2018

Mammography reduces breast cancer mortality, but in some cases breast cancer is detected between screening exams after a negative mammogram – termed ‘interval cancer.’ We examined mammography outcomes for over 300,000 women and found that though the rate of interval cancer was small (5.9 per 10,000), these cancers tended to have poorer prognosis than screen detected cancers. Breast density increased risk of interval cancer, but breast density was not a good predictor of prognosis. Poor prognosis interval cancers were more likely to be diagnosed among women in their 40s compared to older women. We are currently looking for additional risk factors for poor prognosis interval cancers, so that high-risk women can take additional steps to prevent and detect breast cancer.

(Summary submitted by Anne Marie McCarthy, PhD, of the Department of Medicine)

NEW INSIGHTS INTO DEVELOPMENT OF HUMAN LANGUAGE 

Neural Encoding and Production of Functional Morphemes in the Posterior Temporal Lobe
Lee DK, Fedorenko E, Simon MV, Curry WT, Nahed BV, Cahill DP, Williams ZM
Published in Nature Communications on May 14, 2018

The study identifies a small area within the human posterior temporal lobe that is essential for the natural production of language. By using neural recording and stimulation techniques, we find that transient inhibition of this area impairs our ability to produce words with appropriate meaning but does not affect other linguistic processes such as comprehension or articulation. Detailed understanding of this brain area may help improve our ability to diagnose and treat disorders such as dyslexia, traumatic brain injury and stroke in which language production is often affected.

(Summary submitted by Ziv Williams, MD, of the Department of Neurosurgery)

DISSECTING THE RNA COPYING PROCESS

Crystallographic Observation of Nonenzymatic RNA Primer Extension
Zhang W, Walton T, Li L, Szostak JW
Published in eLife on May 31, 2018

Modern cells use complex enzymes to replicate their DNA and copy DNA into RNA, and because of the importance of these enzymes, they have been studied in great detail. X-ray crystallography has been particularly useful in allowing scientists to see, at an atomic level of detail, the various chemical steps in these central biological processes. In contrast, the chemical copying of RNA sequences without enzymes, which is thought to have been critical for the origin of life, is much less well understood. In this paper, we used x-ray crystallography to watch RNA molecules go through a series of chemical changes during the copying reaction, revealing for the first time an atomic level picture of this critical process.

(Summary submitted by Jack Szostak, PhD, of the Department of Genetics)

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