Tag: mutations

The Tragic Life Of Lucia Zarate: The Smallest Woman Ever

Lucia Zarate was a popular sideshow performer in the late 1800s and was billed as the human doll for the fact that she was only 24 inches tall and weighed only 4.7 pounds, a world record to this day.

Learning about Lucia tells us a lot about how the shortest person in the world is determined. It’s more complicated than you think.

The Most Inbred People Of All Time | Random Thursday

From the most powerful royalty in history to an uncontacted village in New York State, we’re talking about some of the most inbred people of all time.

The Blue Fugates of Kentucky were an isolated group of settlers who, through a rare recessive gene, developed blue skin. Due to their blue skin and their isolated location, they began to inbreed, eventually becoming something of a local legend – the blue hillbillies that live in the woods – until they reappeared in the 1960s.

Allentown, New York, is a village in New York State that was cut off from the rest of society after a dam flooded the valley where they lived. They call their community The Hollow, but outsiders call it Allentown because almost everybody there is from the same family.

The Habsburgs of Europe were one of the most powerful families in history, ruling over the Holy Roman Empire in Eastern Europe until the early 20th century. But one segment of the Habsburgs in Spain, known as the Spanish Habsburgs, participated in incest and inbreeding for so long that they developed The Habsburg Jaw – a genetic deformity that got so bad that many could barely speak. It was Charles II of Spain that finally put an end to this practice because he was so inbred that he couldn’t reproduce.

And the Egyptian royal family of ancient Egypt practiced inbreeding for over a thousand years because they believed that the only person who could mate with a pharaoh was someone else from their family – they were living gods after all. By the time King Tutankhamen was born, their lineage was so ruined that he had multiple genetic deformities and died at only 18.

Taking Gene-Editing To The Next Level

Researchers who discovered a molecular “scissors” for snipping genes have now developed a similar approach for targeting and cutting RNA.

The new cutting tool should help researchers better understand RNA’s role in cells and diseases, and some believe it could one day be useful in treatments for illnesses from Huntington’s to heart disease.

To develop the “blades” for the process, researchers led by Feng Zhang at the Broad Institute used CRISPR (clustered regularly interspaced short palindromic repeats)—a system that bacteria evolved to fight off pathogens.

CRISPR has previously been used to edit DNA but had been theorized to work on RNA as well.

The new findings, reported Thursday in Science, came from systematically exploring different aspects of that natural defense system that protects bacteria—and may eventually be put to use helping people.

Nature has already invented all these really interesting mechanisms,” Zhang says, comparing himself with a treasure hunter.

We’re just trying to play with that and learn how they work…then turn them into tools that will be useful to us.


Zhang says the new paper will not affect an ongoing patent dispute over who owns rights to the gene-editing approach known as CRISPR–Cas9. His team was the first to use CRISPR–Cas9 in mammalian cells.

Another team—led by Jennifer Doudna, at the University of California, Berkeley, and French researcher Emmanuelle Charpentier—was first to publish on CRISPR–Cas9, showing its activity in bacteria.

Ironically, Doudna was a co-author on a March paper in Cell that used CRISPR–Cas9 to cut RNA in mammalian cells whereas Zhang’s new paper focuses on bacteria.

The two RNA manipulation methods may be complementary ways to approach the same ends or one may turn out to be more efficient than the other.

In interviews this week each group praised the other’s work while touting the advantages of their own respective approaches.

Zhang says his new method—using the enzyme C2c2 to target RNA—relies on an existing natural system and therefore may be more effective than an approach that requires more manipulation.

Gene Yeo, senior author on the Cell paper, says he has collaborated with both Doudna and Zhang, and described the new paper as a continuation of the kind of “friendly competition” that drives science.

There’s always a bit of a race between a lot of the groups, including mine,” he says. “I think scientific competition is good. People tend to push the boundaries more.

Although Yeo pointed out that the C2c2 system has not yet been shown to work in mammalian cells, Zhang says unpublished results make him optimistic that it will.

Both RNA-targeting approaches have a long way to go before they could be tested in people—but the promise is there, says Yeo, a professor of cellular and molecular medicine at the University of California, San Diego.

Targeting RNA may also offer new insights into how changes in RNA lead to changes in biology and the development of disease.

I think we’ll see an avalanche of these tools that will enable us to monitor and study RNA,” Yeo says.

This helps us think about RNA as not just an intermediate molecule between DNA and protein,” but as a therapeutic tool for treating diseases and problems of development.

Genes consist of double-stranded DNA, which makes single-stranded RNA—which in turn makes the proteins needed for life. Many diseases result from too much or too little protein.

Theoretically, acting on the RNA could push those protein levels up or down, thereby offering treatments.

Manipulating RNA poses fewer ethical concerns than tinkering with the underlying DNA, although gene editing will remain a better approach for treating some diseases.

The problem with DNA editing is that it’s permanent,” Yeo says. “That could be good, but what if you make a mistake?

In some cases, such as with brain cells, DNA repair mechanisms are so strong that it may be more effective to act on the RNA rather than cutting the DNA, says Yeo, who has started a company that’s still in stealth mode to begin looking at treating diseases with this approach.

Zhang says he has long been interested in developing systems to target RNA. His team decided to survey the different kinds of CRISPR systems to figure out their functions.

C2c2 turned out to be an RNA-targeting system, according to the new study, which includes researchers from the National Institutes of Health, Rutgers University and the Skolkovo Institute of Science and Technology in Russia, in addition to Harvard University and Massachusetts Institute of Technology.

Like the Cas9 system that targets specific DNA, C2c2 can be aimed directly at desired RNA sequences, with seemingly few off-target effects.

The reason that it has evolved is to be able to use RNA guides to target RNA,” Zhang says.

His colleague, Eugene Koonin, a co-author on the new paper, puts it more poetically: “Evolution of life to a very large extent is a story of host–parasite interactions,” says Koonin, an expert in evolutionary genomics at the National Center for Biotechnology Information.

As we explore this arms race between host and parasite, we discover more and more intricate, novel ways in which cellular organisms cope with parasites and parasites counteract.

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Pass it on: New Scientist

Humans Are Still Evolving—And We Can Watch It Happen

Many people think evolution requires thousands or millions of years, but biologists know it can happen fast.

Now, thanks to the genomic revolution, researchers can actually track the population-level genetic shifts that mark evolution in action—and they’re doing this in humans.

Two studies presented at the Biology of Genomes meeting here last week show how our genomes have changed over centuries or decades, charting how since Roman times the British have evolved to be taller and fairer, and how just in the last generation the effect of a gene that favors cigarette smoking has dwindled in some groups.

Being able to look at selection in action is exciting,” says Molly Przeworski, an evolutionary biologist at Columbia University.

The studies show how the human genome quickly responds to new conditions in subtle but meaningful ways, she says. “It’s a game-changer in terms of understanding evolution.”

Evolutionary biologists have long concentrated on the role of new mutations in generating new traits. But once a new mutation has arisen, it must spread through a population.

Every person carries two copies of each gene, but the copies can vary slightly within and between individuals. Mutations in one copy might increase height; those in another copy, or allele, might decrease it.

If changing conditions favor, say, tallness, then tall people will have more offspring, and more copies of variants that code for tallness will circulate in the population.

With the help of giant genomic data sets, scientists can now track these evolutionary shifts in allele frequencies over short timescales.

Jonathan Pritchard of Stanford University in Palo Alto, California, and his postdoc Yair Field did so by counting unique single-base changes, which are found in every genome.

Such rare individual changes, or singletons, are likely recent, because they haven’t had time to spread through the population.

Because alleles carry neighboring DNA with them as they circulate, the number of singletons on nearby DNA can be used as a rough molecular clock, indicating how quickly that allele has changed in frequency.

Pritchard’s team analyzed 3000 genomes collected as part of the UK10K sequencing project in the United Kingdom. For each allele of interest in each genome, Field calculated a “singleton density score” based on the density of nearby single, unique mutations.

The more intense the selection on an allele, the faster it spreads, and the less time there is for singletons to accumulate near it. The approach can reveal selection over the past 100 generations, or about 2000 years.

Stanford graduate students Natalie Telis and Evan Boyle and postdoc Ziyue Gao found relatively few singletons near alleles that confer lactose tolerance—a trait that enables adults to digest milk—and that code for particular immune system receptors.

Among the British, these alleles have evidently been highly selected and have spread rapidly.

The team also found fewer singletons near alleles for blond hair and blue eyes, indicating that these traits, too, have rapidly spread over the past 2000 years, Field reported in his talk and on 7 May in the preprint server bioRxiv.org.

One evolutionary driver may have been Britain’s gloomy skies: Genes for fair hair also cause lighter skin color, which allows the body to make more vitamin D in conditions of scarce sunlight.

Or sexual selection could have been at work, driven by a preference for blond mates.

Other researchers praise the new technique.

This approach seems to allow much more subtle and much more common signals of selection to be detected,” says evolutionary geneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

In a sign of the method’s power, Pritchard’s team also detected selection in traits controlled not by a single gene, but by tiny changes in hundreds of genes.

Among them are height, head circumference in infants, and hip size in females—crucial for giving birth to those infants.

By looking at the density of singletons flanking more than 4 million DNA differences, Pritchard’s team discovered that selection for all three traits occurred across the genome in recent millennia.

Joseph Pickrell, an evolutionary geneticist at New York Genome Center in New York City, has used a different strategy to put selection under an even keener microscope, detecting signs of evolution on the scale of a human lifetime.

He and Przeworski took a close look at the genomes of 60,000 people of European ancestry who had been genotyped by Kaiser Permanente in Northern California, and 150,000 people from a massive U.K. sequencing effort called the UK Biobank.

They wanted to know whether genetic variants change frequency across individuals of different ages, revealing selection at work within a generation or two.

The biobank included relatively few old people, but it did have information about participants’ parents, so the team also looked for connections between parental death and allele frequencies in their children.

In the parents’ generation, for example, the researchers saw a correlation between early death in men and the presence in their children (and therefore presumably in the parents) of a nicotine receptor allele that makes it harder to quit smoking.

Many of the men who died young had reached adulthood in the United Kingdom in the 1950s, a time when many British men had a pack-a-day habit.

In contrast, the allele’s frequency in women and in people from Northern California did not vary with age, presumably because fewer in these groups smoked heavily and the allele did not affect their survival.

As smoking habits have changed, the pressure to weed out the allele has ceased, and its frequency is unchanged in younger men, Pickrell explains.

My guess is we are going to discover a lot of these gene-by-environment effects,” Przeworski says.

Indeed, Pickrell’s team detected other shifts. A set of gene variants associated with late-onset menstruation was more common in longer-lived women, suggesting it might help delay death.

Pickrell also reported that the frequency of the ApoE4 allele, which is associated with Alzheimer’s disease, drops in older people because carriers died early.

We can detect selection on the shortest timeframe possible, an individual’s life span,” he says.

Signs of selection on short timescales will always be prey to statistical fluctuations.

But together the two projects “point to the power of large studies to understand what factors determine survival and reproduction in humans in present-day societies,” Pääbo says.

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Pass it on: Popular Science