Posts Tagged ‘genetics’

by Linda Geddes

You need only to look at families to see that height is inherited — and studies of identical twins and families have long confirmed that suspicion. About 80% of variation in height is down to genetics, they suggest. But since the human genome was sequenced nearly two decades ago, researchers have struggled to fully identify the genetic factors responsible.

Studies seeking the genes that govern height have identified hundreds of common gene variants linked to the trait. But the findings also posed a quandry: each variant had a tiny effect on height that together didn’t amount to the genetic contribution predicted by family studies. This phenomenon, which occurs for many other traits and diseases, was dubbed missing heritability, and had even prompted some researchers to speculate that there’s something fundamentally wrong with our understanding of genetics.

Now, a study suggests that most of the missing heritability for height and body mass index (BMI) can, as some researchers had suspected, be found in rarer gene variants that had lain undiscovered until now.

“It is a reassuring paper because it suggests that there isn’t something terribly wrong with genetics,” says Tim Spector, a genetic epidemiologist at King’s College London. “It’s just that sorting it out is more complex than we thought.” The research was posted1 to the bioRxiv preprint server on 25 March.

Scouring the genome

To seek out the genetic factors that underlie diseases and traits, geneticists turn to mega-searches known as genome-wide association studies (GWAS). These scour the genomes of, typically, tens of thousands of people — or, increasingly, more than a million — for single-letter changes, or SNPs, in genes that commonly appear in individuals with a particular disease or that could explain a common trait such as height.

But GWAS have limitations. Because sequencing the entire genomes of thousands of people is expensive, GWAS themselves scan only a strategically selected set of SNPs, perhaps 500,000, in each person’s genome. That’s only a snapshot of the roughly six billion nucleotides — the building blocks of DNA — strung together in our genome. In turn, these 500,000 common variants would have been found from sequencing the genomes of just a few hundred people, says Timothy Frayling, a human geneticist at the University of Exeter, UK.

A team led by Peter Visscher at the Queensland Brain Institute in Brisbane, Australia, decided to investigate whether rarer SNPs than those typically scanned in GWAS might explain the missing heritability for height and BMI. They turned to whole-genome sequencing — performing a complete readout of all 6 billion bases — of 21,620 people. (The authors declined to comment on the preprint, because it is under submission at a journal.)

They relied on the simple, but powerful, principle that all people are related to some extent — albeit distantly — and that DNA can be used to calculate degrees of relatedness. Then, information on the people’s height and BMI could be combined to identify both common and rare SNPs that might be contributing to these traits.

Say, for instance, that a pair of third cousins is closer in height than a pair of second cousins is in a different family: that’s an indication that the third cousins’ height is mostly down to genetics, and the extent of that correlation will tell you how much, Frayling explains. “They used all of the genetic information, which enables you to work out how much of the relatedness was due to rarer things as well as the common things.”

As a result, the researchers captured genetic differences that occur in only 1 in 500, or even 1 in 5,000, people.

And by using information on both common and rare variants, the researchers arrived at roughly the same estimates of heritability as those indicated by twin studies. For height, Visscher and colleagues estimate a heritability of 79%, and for BMI, 40%. This means that if you take a large group of people, 79% of the height differences would be due to genes rather than to environmental factors, such as nutrition.

Complex processes

The researchers also suggest how the previously undiscovered variants might be contributing to physical traits. Tentatively, they found that these rare variants were slightly enriched in protein-coding regions of the genome, and that they had an increased likelihood of being disruptive to these regions, notes Terence Capellini, an evolutionary biologist at Harvard University in Cambridge, Massachusetts. This indicates that the rare variants might partly influence height by affecting protein-coding regions instead of the rest of the genome — the vast majority of which does not include instructions for making proteins, but might influence their expression.

The rarity of the variants also suggests that natural selection could be weeding them out, perhaps because they are harmful in some way.

The complexity of heritability means that understanding the roots of many common diseases — necessary if researchers are to develop effective therapies against them — will take considerably more time and money, and it could involve sequencing hundreds of thousands or even millions of whole genomes to identify the rare variants that explain a substantial portion of the illnesses’ genetic components.

The study reveals only the total amount of rare variants contributing to these common traits — not which ones are important, says Spector. “The next stage is to go and work out which of these rare variants are important for traits or diseases that you want to get a drug for.”

Nature 568, 444-445 (2019)

doi: 10.1038/d41586-019-01157-y

https://www.nature.com/articles/d41586-019-01157-y?utm_source=Nature+Briefing&utm_campaign=26855a4182-briefing-dy-20190424&utm_medium=email&utm_term=0_c9dfd39373-26855a4182-44039353

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by Mike McRae

Earth might have a dizzying array of life forms, but our biology ultimately remains a solitary data point – we simply don’t have a reference for life based on DNA different from our own. Now, scientists have taken matters into their hands to push the boundaries on what life could be like.

Research funded by NASA and led by the Foundation for Applied Molecular Evolution in the US has led to the creation of an entirely new flavour of the DNA double helix, one that has an additional four nucleotide bases.

It’s being called hachimoji DNA (from the Japanese words for ‘eight letters’) and it includes two new pairs to add to the existing partnerships of adenine (A) paired with thymine (T), and guanine (G) with cytosine (C).

This work to expand on nature’s own genetic recipe might sound a little familiar. The same scientists already successfully squeezed in two new letters in 2011. Only last year yet another version of an extended alphabet, also with six letters, was made to function inside a living organism.

Now, in what might seem like a case of overachievement, researchers have gone back to the drawing board to develop even more non-standard nucleotides.

They have a purpose for doubling the number of codes in the recipe book, though.

“By carefully analysing the roles of shape, size and structure in hachimoji DNA, this work expands our understanding of the types of molecules that might store information in extraterrestrial life on alien worlds,” says chemist Steven Benner.

We already know a lot about the stability and functionality of ‘natural’ DNA under a range of environmental conditions, and are slowly teasing apart possible scenarios describing its evolution from simpler organic materials to living chemistry.

But to really get a good sense of how a genetic system could evolve, we need to test the limits of its underlying chemistry.

Hachimoji DNA certainly allows for that. The new codes, labelled P, B, Z and S, are based on the same kind of nitrogenous molecules as existing ones, categorised as purines and pyrimidines.

Similarly, they link up with hydrogen bonds to form their own base pairs – S bonding with B, and P with Z.

That’s where the similarities fade out. These new ‘letters’ introduce dozens of new chemical parameters to the double helix structure that potentially affect how it zips and twists.

By devising models that predict the molecule’s stability and then observing actual structures made of this ‘alien’ DNA, researchers are better equipped what’s truly important when it comes to the fundamentals of a genetic template.

The researchers constructed hundreds of hachimoji helices made up of different configurations of natural and synthetic bases and then subjected them to a range of conditions to see how well they held up.

While there were a few minor differences in how the new letters behaved, there was no reason to believe hachimoji DNA wouldn’t work well as an information-carrying template that could mutate and evolve.

The team not only showed their synthetic letters could contribute to new codes without swiftly disintegrating, the sequences were also translated into synthetic RNA versions.

Their work falls well short of a second genesis. But a novel DNA format such as this is a step towards determining what living chemistry might – and might not – look like elsewhere in the Universe.

“Life detection is an increasingly important goal of NASA’s planetary science missions, and this new work will help us to develop effective instruments and experiments that will expand the scope of what we look for,” says NASA’s Planetary Science Division’s acting director, Lori Glaze.

Devising new bases that can operate alongside our own DNA also has applications closer to home, not only as a way to reprogram life with a different code base, but in our effort to build new kinds of nanostructures.

The sky really isn’t the limit with synthetic DNA. This is going to take us to the stars and back again.

This research was published in Science.

https://www.sciencealert.com/scientists-made-synthetic-dna-using-8-letters-and-it-could-help-us-find-aliens

by David Nield

Scientists are genetically modifying mosquitoes in a high-security lab – and they’re hoping the insects will help wipe out some of the mosquito-borne diseases that continue to plague communities worldwide.

It’s known as a gene drive: where mosquitoes modified to be incapable of passing on a particular virus are used to replace the existing population of insects over several generations, with the modified genes being passed on to all their offspring.

The idea has attracted controversy because it messes with the fundamentals of nature, but it’s now under consideration by the World Health Organisation (WHO). This particular testing has entered a new phase, NPR reports, with a large-scale release of genetically modified mozzies inside a facility in Terni, Italy.

“This will really be a breakthrough experiment,” entomologist Ruth Mueller, who runs the lab, told Rob Stein at NPR. “It’s a historic moment. It’s very exciting.”

Using the ‘molecular scissor’ editing technique CRISPR, a gene known as “doublesex” in the bugs has been altered. The gene transforms female mosquitoes, taking away their biting ability and making them infertile.

At the moment, the bugs are being released in cages designed to replicate their natural environments, with hot and humid air, and places to shelter. Artificial lights are used to simulate sunrise and sunset.

The idea is to see if the mosquitoes with CRISPR-edited genetic code can wipe out the unmodified insects inside the cages. It follows on from previous proof-of-concept studies that we’ve seen before.

Ultimately these mosquitoes could be released in areas hit by malaria, bringing the local mozzie population crashing down and saving human lives. The disease is responsible for more than 400,000 deaths every year – mostly young children.

Reducing those figures sounds like a great idea, so why the controversy? Well, many scientists are urging caution when it comes to altering genetic code at this fundamental level – we just don’t know what impact these genetically edited mosquitoes will have on the world around them.

For that reason the lab has been designed to minimise any chance that the specially engineered mosquitoes could escape. The testing has also been specifically located in Italy, where this mosquito species – Anopheles gambiae – wouldn’t be able to survive outside in the natural climate.

“This is a technology where we don’t know where it’s going to end,” Nnimmo Bassey, director of the Health of Mother Earth Foundation in Nigeria, told NPR. “We need to stop this right where it is. They’re trying to use Africa as a big laboratory to test risky technologies.”

Some experts think adding genetically modified mosquitoes to natural ecosystems could harm other plants and animals that depend on them. There are a lot of unknowns.

The team behind the new experiments counters the critique by saying they’re working slowly and methodically – and that the potential side effects are outweighed by the benefits of eradicating malaria.

At the moment scientists are targeting just one species of mosquito out of hundreds, and several more years of research and consultation are planned before genetically edited mozzies would ever be released.

“There’s going to be concerns with any technology,” one of the research team, Tony Nolan from Imperial College London in the UK, told NPR.

“But I don’t think you should throw out a technology without having done your best to understand what its potential is to be transformative for medicine. And, were it to work, this would be transformative.”

https://www.sciencealert.com/scientists-take-first-step-in-controversial-mosquito-gene-drive-experiment

After scientists unlocked the secrets of the human genome in 2003, there was immediate concern about how that knowledge might be abused in the wrong hands. Now, an East Bay entrepreneur wants to put that power in everyone’s hands.

Dr. Josiah Zayner has a PhD in biochemistry and worked for NASA, engineering organisms to help astronauts survive on Mars. But that wasn’t innovative enough for the young, self-described “Bio Hacker.”

“Normal scientists want to study, like, how fruit flies have sex or something, something that nobody really cares about,” said Dr. Zayner. “And what I want to study is, how do we make dragons or super-humans or something like that?”

Zayner wants others to do it as well. Out of a West Oakland apartment, he operates a company called The Odin that sells “gene-editing” kits; they come with all that’s necessary to create your own Genetically Modified Organism.

The kit teaches novice scientists how to inject tree frogs with a type of human growth enzyme that causes the frogs to double in size in about a month.

“It sounds ridiculous,” Dr. Zayner said, “but we’ve been doing gene therapy on human beings since the late 90’s, right? The stuff works, we know how to do it, I want to teach people that. I want people to see how it works.”

But at St. Mary’s College in Moraga, biology professor Vidya Chandrasekaran says there are ethical concerns about an untrained person using a live animal for experimentation.

“Using it in this manner, I’m not sure is the right way to approach biology,” she said.

Dr. Zayner frequently uses himself as a guinea pig. He once injected himself with a growth accelerator while live-streaming a talk at a bio conference. Dr. Chandrasekaran said that’s the kind of thing that occurs when people use science without accountability.

“It really matters whether the people who are doing these things understand the implications and the outcome of it,” she said.

But according to Dr. Zayner, new and powerful technologies are always feared at their beginnings. He pointed out that computers were once giant machines used only by business, government and universities.

“And if you ask yourself now, ‘Was it the correct thing to do to allow people to have access to computers?’, there’s nobody in the world who would say no,” he said.

“When you make a technology available to everybody, innovation happens.”

Whether gene-altering technology for the masses is the next innovation or a case of science gone mad is a question that only time will answer.

East Bay Biochemist Sells ‘Gene-Editing Kit’ For The Masses

Thank to Kebmodee for bringing this to the It’s Interesting community.


Patterns of gene expression unite the prairie vole Microtus ochrogaster with other monogamous species, including certain frogs, fish, and birds. YVA MOMATIUK AND JOHN EASTCOTT/MINDEN PICTURES

By Kelly Servick

In the animal world, monogamy has some clear perks. Living in pairs can give animals some stability and certainty in the constant struggle to reproduce and protect their young—which may be why it has evolved independently in various species. Now, an analysis of gene activity within the brains of frogs, rodents, fish, and birds suggests there may be a pattern common to monogamous creatures. Despite very different brain structures and evolutionary histories, these animals all seem to have developed monogamy by turning on and off some of the same sets of genes.

“It is quite surprising,” says Harvard University evolutionary biologist Hopi Hoekstra, who was not involved in the new work. “It suggests that there’s a sort of genomic strategy to becoming monogamous that evolution has repeatedly tapped into.”

Evolutionary biologists have proposed various benefits to so-called social monogamy, where mates pair up for at least a breeding season to care for their young and defend their territory. When potential mates are scarce or widely dispersed, for example, forming a single-pair bond can ensure they get to keep reproducing.

Neuroscientist Hans Hofmann and evolutionary biologist Rebecca Young at the University of Texas in Austin wanted to explore how the regulation of genes in the brain might have changed when a nonmonogamous species evolved to become monogamous. For example, the complex set of genes that underlie the ability to tolerate the presence of another member of one’s species presumably exists in nonmonogamous animals, but might be activated in different patterns to allow prolonged partnerships in monogamous ones.

“We wanted to be bold—and maybe a little bit crazy” in the new experiment, Hofmann says. Instead of doing a relatively straightforward genetic comparison between closely related species on either side of the monogamy divide, he and colleagues wanted to hunt down a gene activity signature associated with monogamy in males across a wide variety of species—frogs, mice, voles, birds, and fish. So in each of these groups, they selected two species, one monogamous and one nonmonogamous.

Rounding up the brains of those animals took an international team and years of effort. Hostile regional authorities and a complicated permitting system confronted the team in Romania as they tried to capture two types of a native songbird. Hofmann donned scuba gear and plunged into Africa’s Lake Tanganyika to chase finger-length cichlid fish into nets. Delicately debraining them while aboard a rocking boat, he says, was a struggle.

Back the lab, the researchers then grouped roughly comparable genes across all 10 species based on similarities in their sequences. For each of these cross-species gene groups, they measured activity based on how much the cells in the brain transcribed the DNA’s proteinmaking instructions into strands of RNA.

Among the monogamous animals, a pattern emerged. The researchers found certain sets of genes were more likely to be “turned up” or “turned down” in those creatures than in the nonmonogamous species. And they ruled out other reasons why these monogamous animals might have similar gene expression patterns, including similar environments or close evolutionary relationships.

Among the genes with increased activity in monogamous species were those involved in neural development, signaling between cells, learning, and memory, the researchers report online today in the Proceedings of the National Academy of Sciences. They speculate that genes that make the brain more adaptable—and better able to remember—might also help animals recognize their mates and find their presence rewarding.

It makes sense that genes involved in brain development and function would underlie a complex behavior like monogamy, says behavioral neuroscientist Claudio Mello of Oregon Health & Science University in Portland. But because the researchers didn’t dissect out specific brain regions and analyze their RNA production independently, they can’t describe the finely tuned patterns of gene expression in areas that are key to reproductive behavior. “It seems to me unlikely that by themselves these genes will be able to ‘explain’ this behavior,” he says.

“The fact that they got any common genes at all is interesting,” adds Lisa Stubbs, a developmental geneticist at the University of Illinois in Urbana. “It is a superb data set and an expert analysis,” she says, “[but] the authors have not actually uncovered many important biological insights into monogamy.”

The study did turn up a curious outlier. Some of the genes with decreased expression in most of the monogamous species showed increased expression in one of them—the poison dart frog Ranitomeya imitator. Young notes that in this species’s evolutionary history, fathers cared for the young before cooperative parenting evolved. As a result, these frogs may have had a different evolutionary starting point than other animals in the study, later tapping into different genes to become monogamous.

Hoekstra, who has studied the genetics of monogamy in mice, sees “a lot of exciting next steps.” There are likely mutations in other regions of DNA that regulate the expression of the genes this study identified. But it will take more work to show a causal relationship between any particular genetic sequence and monogamous behavior.

People also often opt for monogamy, albeit for a complicated set of social and cultural reasons. So, do we share the gene activity signature common to monogamous birds, fish, and frogs? “We don’t know that,” says Hofmann, but “we certainly would speculate that the kind of gene expression patterns … might [show up] in humans as well.”

http://www.sciencemag.org/news/2019/01/monogamy-may-have-telltale-signature-gene-activity

zanzara-anopheles-gambiae-720-x

by ASHLEY YEAGER

A gene drive has successfully caused the collapse of a malaria-carrying mosquito population in the lab, researches report today (September 24) in Nature Biotechnology. This is the first time a gene drive—a genetic element that ensures its own inheritance—has caused a population of mosquitoes to self-destruct, a result that holds promise for combating malaria.

“This breakthrough shows that gene drive can work, providing hope in the fight against a disease that has plagued mankind for centuries,” study coauthor Andrea Crisanti, a molecular parasitologist at Imperial College London, says in a university statement.

In the study, the team targeted a region of a gene called doublesex that is responsible for female development. Female Anopheles gambiae mosquitoes with two copies of the altered doublesex gene did not lay eggs. After eight generations, the drive had spread through the entire population, such that no eggs were laid.

“It’s a really stunning development,” Omar Akbari, an entomologist at the University of California, Irvine who was not involved to the study, tells Wired, noting that mosquitoes are under “huge evolutionary pressure” to resist gene drives that cause the population to collapse. However, Akbari tells Science News that this gene drive might not work well in the wild because resistance will probably pop up.

Crisanti, however, is more confident. “We are not saying this is 100 percent resistance-proof,” he tells The New York Times. “But it looks very promising.” Still, he adds in the university statement, “[i]t will still be at least 5-10 years before we consider testing any mosquitoes with gene drive in the wild.” First, his team will need to test the gene drive in larger containers, where the mosquitoes can act more naturally, Crisanti tells Wired—swarming to find a mate, for instance. Such details were difficult to mimic in the 20 cubic centimeter cages used in this study.

Despite the need for further testing, some researchers hailed the current study as a major success. “With this achievement,” Kevin Esfelt, who studies the evolution of gene drives at MIT, tells The New York Times, “the major barriers to saving [human] lives are arguably no longer mostly technical, but social and diplomatic.”

https://www.the-scientist.com/news-opinion/study–gene-drive-wipes-out-lab-mosquitoes-64849

largest-ever-study-of-genetic-links-to-depression-and-anxiety-launched-309700

The NIHR and King’s College London are calling for 40,000 people diagnosed with depression or anxiety to enrol online for the Genetic Links to Anxiety and Depression (GLAD) Study and join the NIHR Mental Health Bioresource.

Researchers hope to establish the largest ever database of volunteers who can be called up to take part in research exploring the genetic factors behind the two most common mental health conditions – anxiety and depression.

[youtube=https://youtu.be/wzgvS8gU2Ss\

The GLAD study will make important strides towards better understanding of these disorders and provide a pool of potential participants for future studies, reducing the time-consuming process of recruiting patients for research.

Research has shown 30-40% of the risk for both depression and anxiety is genetic and 60-70% due to environmental factors. Only by having a large, diverse group of people available for studies will researchers be able to determine how genetic and environmental triggers interact to cause anxiety and depression.

Leader of the GLAD study and the NIHR Mental Health BioResource, Dr Gerome Breen of King’s College London, said: “It’s a really exciting time to become involved in mental health research, particularly genetic research which has made incredible strides in recent years – we have so far identified 46 genetic links for depression and anxiety.

“By recruiting 40,000 volunteers willing to be re-contacted for research, the GLAD Study will take us further than ever before. It will allow researchers to solve the big unanswered questions, address how genes and environment act together and help develop new treatment options.”

The GLAD Study, a collaboration between the NIHR BioResource and King’s College London, has been designed to be particularly accessible, with a view to motivating more people to take part in mental health research.

Research psychologist and study lead Professor Thalia Eley, King’s College London, said: “We want to hear from all different backgrounds, cultures, ethnic groups and genders, and we are especially keen to hear from young adults. By including people from all parts of the population, what we learn will be relevant to everyone. This is a unique opportunity to participate in pioneering medical science.”

https://www.nihr.ac.uk/news/nihr-launches-largest-ever-study-of-genetic-links-to-depression-and-anxiety/9201