Missing Genes Point to Possible Drug Targets

Human knockout projectEvery person’s genetic blueprint, or genome, is unique because of variations that occasionally occur in our DNA sequences. Most of those are passed on to us from our parents. But not all variations are inherited—each of us carries 60 to 100 “new mutations” that happened for the first time in us. Some of those variations can knock out the function of a gene in ways that lead to disease or other serious health problems, particularly in people unlucky enough to have two malfunctioning copies of the same gene. Recently, scientists have begun to identify rare individuals who have loss-of-function variations that actually seem to improve their health—extraordinary discoveries that may help us understand how genes work as well as yield promising new drug targets that may benefit everyone.

In a study published in the journal Nature, a team partially funded by NIH sequenced all 18,000 protein-coding genes in more than 10,500 adults living in Pakistan [1]. After finding that more than 17 percent of the participants had at least one gene completely “knocked out,” researchers could set about analyzing what consequences—good, bad, or neutral—those loss-of-function variations had on their health and well-being.

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Creative Minds: A New Mechanism for Epigenetics?

Keith Maggert

Keith Maggert

To learn more about how DNA and inheritance works, Keith Maggert has spent much of his nearly 30 years as a researcher studying what takes place not just within the DNA genome but also the subtle modifications of it. That’s where a stable of enzymes add chemical marks to DNA, turning individual genes on or off without changing their underlying sequence. What’s really intrigued Maggert is these “epigenetic” modifications are maintained through cell division and can even get passed down from parent to child over many generations. Like many researchers, he wants to know how it happens.

Maggert thinks there’s more to the story than scientists have realized. Now an associate professor at the University of Arizona College of Medicine, Tucson, he suspects that a prominent subcellular structure in the nucleus called the nucleolus also exerts powerful epigenetic effects. What’s different about the nucleolus, Maggert proposes, is it doesn’t affect genes one by one, a focal point of current epigenetic research. He thinks under some circumstances its epigenetic effects can activate many previously silenced, or “off” genes at once, sending cells and individuals on a different path toward health or disease.

Maggert has received a 2016 NIH Director’s Transformative Research Award to pursue this potentially new paradigm. If correct, it would transform current thinking in the field and provide an exciting new perspective to track epigenetics and its contributions to a wide range of human diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.

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Random Mutations Play Major Role in Cancer

Cancer OddsWe humans are wired to search for a causative agent when something bad happens. When someone develops cancer, we seek a reason. Maybe cancer runs in the family. Or perhaps the person smoked, never wore sunscreen, or drank too much alcohol. At some level, those are reasonable assumptions, as genes, lifestyle, and environment do play important roles in cancer. But a new study claims that the reason why many people get cancer is simply just bad luck.

This bad luck occurs during the normal process of cell division that is essential to helping our bodies grow and remain healthy. Every time a cell divides, its 6 billion letters of DNA are copied, with a new copy going to each daughter cell. Typos inevitably occur during this duplication process, and the cell’s DNA proofreading mechanisms usually catch and correct these typos. However, every once in a while, a typo slips through—and if that misspelling happens to occur in certain key areas of the genome, it can drive a cell onto a pathway of uncontrolled growth that leads to cancer. In fact, according to a team of NIH-funded researchers, nearly two-thirds of DNA typos in human cancers arise in this random way.

The latest findings should help to reassure people being treated for many forms of cancer that they likely couldn’t have prevented their illness. They also serve as an important reminder that, in addition to working on better strategies for prevention, cancer researchers must continue to pursue innovative technologies for early detection and treatment.

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Out of Africa: DNA Analysis Points to a Single Major Exodus

View of Africa from space

Credit: NASA

If you go back far enough, the ancestors of all people trace to Africa. That much is clear. We are all Africans. But there’s been considerable room for debate about exactly when and how many times modern humans made their way out of Africa to take up residence in distant locations throughout the world. It’s also unclear what evolutionary or other factors might have driven our human ancestors to set off on such a perilous and uncertain journey (or journeys) in the first place.

By analyzing 787 newly sequenced complete human genomes representing more than 280 diverse and understudied populations, three new studies—two of which received NIH funding—now help to fill in some of those missing pages of our evolutionary history. The genomic evidence suggests that the earliest human inhabitants of Eurasia came from Africa and began to diverge genetically at least 50,000 years ago. While the new studies differ somewhat in their conclusions, the findings also lend support to the notion that our modern human ancestors dispersed out of Africa primarily in a single migratory event. If an earlier and ultimately failed voyage occurred, it left little trace in the genomes of people alive today.

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Gene Duplication: New Analysis Shows How Extra Copies Split the Work

Word cloudThe human genome contains more than 20,000 protein-coding genes, which carry the instructions for proteins essential to the structure and function of our cells, tissues and organs. Some of these genes are very similar to each other because, as the genomes of humans and other mammals evolve, glitches in DNA replication sometimes result in extra copies of a gene being made. Those duplicates can be passed along to subsequent generations and, on very rare occasions, usually at a much later point in time, acquire additional modifications that may enable them to serve new biological functions. By starting with a protein shape that has already been fine-tuned for one function, evolution can produce a new function more rapidly than starting from scratch.

Pretty cool! But it leads to a question that’s long perplexed evolutionary biologists: Why don’t duplicate genes vanish from the gene pool almost as soon as they appear? After all, instantly doubling the amount of protein produced in an organism is usually a recipe for disaster—just think what might happen to a human baby born with twice as much insulin or clotting factor as normal. At the very least, duplicate genes should be unnecessary and therefore vulnerable to being degraded into functionless pseudogenes as new mutations arise over time

An NIH-supported team offers a possible answer to this question in a study published in the journal Science. Based on their analysis of duplicate gene pairs in the human and mouse genomes, the researchers suggest that extra genes persist in the genome because of rapid changes in gene activity. Instead of the original gene producing 100 percent of a protein in the body, the gene duo quickly divvies up the job [1]. For instance, the original gene might produce roughly 50 percent and its duplicate the other 50 percent. Most importantly, organisms find the right balance and the duplicate genes can easily survive to be passed along to their offspring, providing fodder for continued evolution.

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