Tag Archives: mutation

BigBang

Good Mutations and Breathing

Van_andel_113

Stem cells — the factories that manufacture all our component body parts — may hold a key to divining why our bodies gradually break down as we age. A new body of research shows how the body’s population of blood stem cells mutates, and gradually dies, over a typical lifespan. Sometimes these mutations turn cancerous, sometimes not. Luckily for us, the research is centered on the blood samples of Hendrikje van Andel-Schipper — she died in 2005 at the age of 115, and donated her body to science. Her body showed a remarkable resilience — no hardening of the arteries and no deterioration of her brain tissue.  When quizzed about the secret of her longevity, she once retorted, “breathing”.

From the New Scientist:

Death is the one certainty in life – a pioneering analysis of blood from one of the world’s oldest and healthiest women has given clues to why it happens.

Born in 1890, Hendrikje van Andel-Schipper was at one point the oldest woman in the world. She was also remarkable for her health, with crystal-clear cognition until she was close to death, and a blood circulatory system free of disease. When she died in 2005, she bequeathed her body to science, with the full support of her living relatives that any outcomes of scientific analysis – as well as her name – be made public.

Researchers have now examined her blood and other tissues to see how they were affected by age.

What they found suggests, as we could perhaps expect, that our lifespan might ultimately be limited by the capacity for stem cells to keep replenishing tissues day in day out. Once the stem cells reach a state of exhaustion that imposes a limit on their own lifespan, they themselves gradually die out and steadily diminish the body’s capacity to keep regenerating vital tissues and cells, such as blood.

Two little cells

In van Andel-Schipper’s case, it seemed that in the twilight of her life, about two-thirds of the white blood cells remaining in her body at death originated from just two stem cells, implying that most or all of the blood stem cells she started life with had already burned out and died.

“Is there a limit to the number of stem cell divisions, and does that imply that there’s a limit to human life?” asks Henne Holstege of the VU University Medical Center in Amsterdam, the Netherlands, who headed the research team. “Or can you get round that by replenishment with cells saved from earlier in your life?” she says.

The other evidence for the stem cell fatigue came from observations that van Andel-Schipper’s white blood cells had drastically worn-down telomeres – the protective tips on chromosomes that burn down like wicks each time a cell divides. On average, the telomeres on the white blood cells were 17 times shorter than those on brain cells, which hardly replicate at all throughout life.

The team could establish the number of white blood cell-generating stem cells by studying the pattern of mutations found within the blood cells. The pattern was so similar in all cells that the researchers could conclude that they all came from one of two closely related “mother” stem cells.

Point of exhaustion

“It’s estimated that we’re born with around 20,000 blood stem cells, and at any one time, around 1000 are simultaneously active to replenish blood,” says Holstege. During life, the number of active stem cells shrinks, she says, and their telomeres shorten to the point at which they die – a point called stem-cell exhaustion.

Holstege says the other remarkable finding was that the mutations within the blood cells were harmless – all resulted from mistaken replication of DNA during van Andel-Schipper’s life as the “mother” blood stem cells multiplied to provide clones from which blood was repeatedly replenished.

She says this is the first time patterns of lifetime “somatic” mutations have been studied in such an old and such a healthy person. The absence of mutations posing dangers of disease and cancer suggest that van Andel-Schipper had a superior system for repairing or aborting cells with dangerous mutations.

Read the entire article here.

Image: Hendrikje van Andel-Schipper, aged 113. Courtesy of Wikipedia.

BigBang

The Missing Linc

LincRNA that is. Recent discoveries hint at the potentially crucial role of this new class of genetic material in embryonic development, cell and tissue differentiation and even speciation and evolution.

[div class=attrib]From the Economist:[end-div]

THE old saying that where there’s muck, there’s brass has never proved more true than in genetics. Once, and not so long ago, received wisdom was that most of the human genome—perhaps as much as 99% of it—was “junk”. If this junk had a role, it was just to space out the remaining 1%, the genes in which instructions about how to make proteins are encoded, in a useful way in the cell nucleus.

That, it now seems, was about as far from the truth as it is possible to be. The decade or so since the completion of the Human Genome Project has shown that lots of the junk must indeed have a function. The culmination of that demonstration was the publication, in September, of the results of the ENCODE project. This suggested that almost two-thirds of human DNA, rather than just 1% of it, is being copied into molecules of RNA, the chemical that carries protein-making instructions to the sub-cellular factories which turn those proteins out, and that as a consequence, rather than there being just 23,000 genes (namely, the bits of DNA that encode proteins), there may be millions of them.

The task now is to work out what all these extra genes are up to. And a study just published in Genome Biology, by David Kelley and John Rinn of Harvard University, helps do that for one new genetic class, a type known as lincRNAs. In doing so, moreover, Dr Kelley and Dr Rinn show just how complicated the modern science of genetics has become, and hint also at how animal species split from one another.

Lincs in the chain

Molecules of lincRNA are similar to the messenger-RNA molecules which carry protein blueprints. They do not, however, encode proteins. More than 9,000 sorts are known, and most of those whose job has been tracked down are involved in the regulation of other genes, for example by attaching themselves to the DNA switches that control those genes.

LincRNA is rather odd, though. It often contains members of a second class of weird genetic object. These are called transposable elements (or, colloquially, “jumping genes”, because their DNA can hop from one place to another within the genome). Transposable elements come in several varieties, but one group of particular interest are known as endogenous retroviruses. These are the descendants of ancient infections that have managed to hide away in the genome and get themselves passed from generation to generation along with the rest of the genes.

Dr Kelley and Dr Rinn realised that the movement within the genome of transposable elements is a sort of mutation, and wondered if it has evolutionary consequences. Their conclusion is that it does, for when they looked at the relation between such elements and lincRNA genes, they found some intriguing patterns.

In the first place, lincRNAs are much more likely to contain transposable elements than protein-coding genes are. More than 83% do so, in contrast to only 6% of protein-coding genes.

Second, those transposable elements are particularly likely to be endogenous retroviruses, rather than any of the other sorts of element.

Third, the interlopers are usually found in the bit of the gene where the process of copying RNA from the DNA template begins, suggesting they are involved in switching genes on or off.

And fourth, lincRNAs containing one particular type of endogenous retrovirus are especially active in pluripotent stem cells, the embryonic cells that are the precursors of all other cell types. That indicates these lincRNAs have a role in the early development of the embryo.

Previous work suggests lincRNAs are also involved in creating the differences between various sorts of tissue, since many lincRNA genes are active in only one or a few cell types. Given that their principal job is regulating the activities of other genes, this makes sense.

Even more intriguingly, studies of lincRNA genes from species as diverse as people, fruit flies and nematode worms, have found they differ far more from one species to another than do protein-coding genes. They are, in other words, more species specific. And that suggests they may be more important than protein-coding genes in determining the differences between those species.

[div class=attrib]Read the entire article after the jump.[end-div]

[div class=attrib]Image: Darwin’s finches or Galapagos finches. Darwin, 1845. Courtesy of Wikipedia.[end-div]