Somos todos mutantes: seres humanos têm média de 60 mutações genéticas

Origem das mutações

A primeira medida direta cobrindo todo o genoma humano revelou que cada um de nós tem pelo menos 60 novas mutações genéticas.

Pela primeira vez, os pesquisadores foram capazes de responder às perguntas: Quantas novas mutações uma criança tem? e Que parcela delas vem da mãe ou do pai?

Os cientistas mediram diretamente o número de mutações em duas famílias, usando toda a sequência genética do Projeto 1000 Genomas.

Forças de mutação

Os resultados confirmam que, conforme esperado, o genoma humano, como todos os genomas, é alterado pelas forças de mutação, ou seja, o nosso DNA é alterado em relação ao DNA de nossos pais.

As mutações que ocorrem nas células do esperma ou do óvulo constituirão novas mutações não vistas em nossos pais.

Em uma palavra, somos todos mutantes.

Embora a maioria da nossa identidade genética venha do remanejamento dos genes de nossos pais, novas mutações são a fonte final onde se geram novas variações biológicas.

Evolução biológica

Encontrar novas mutações é tecnicamente um grande desafio - em média, apenas 1 em cada 100 milhões de letras do nosso DNA é alterada a cada geração.

Medições anteriores da taxa de mutação nos seres humanos baseavam-se na média entre os sexos ou foram feitas ao longo de várias gerações.

Nunca havia sido feita uma medição de novas mutações que passaram de um pai específico para uma criança específica.

Os resultados vieram de um cuidadoso estudo de duas famílias, ambas constituídas por pai, mãe e uma criança. Os pesquisadores procuraram novas mutações presentes no DNA das crianças que estavam ausentes dos genomas dos pais.

Eles classificaram as mutações entre as que ocorreram durante a produção de espermatozoides ou óvulos dos pais, e aquelas que possam ter ocorrido durante a vida da criança: os cientistas acreditam que é a taxa de mutação nos espermatozoides ou óvulos que é importante na evolução.

Surpresa

"Nós sabemos agora que, em algumas famílias, a maioria das mutações virá da mãe e, em outras, a maioria virá do pai. Isto é uma surpresa: acreditava-se que em todas as famílias a maioria das mutações viria do pai, devido ao número adicional de vezes que o genoma tem de ser copiado para fazer um espermatozoide, ao contrário de um ovo," diz o Dr. Matt Hurles, coautor do estudo.

Surpreendentemente, em uma das famílias, 92 por cento das mutações derivou do pai, enquanto, na outra família, apenas 36 por cento eram do pai.

Este resultado traz mais perguntas do que respostas. Serão necessários novos estudos para comparar a idade dos pais ou os fatores ambientais, por exemplo.

Aurora A Kinase May Contribute to Kidney Disease

ScienceDaily (June 13, 2011) — The Aurora A kinase may contribute to polycystic kidney disease (PKD) by inactivating a key calcium channel in kidney cells, according to a study in the June 13 issue of The Journal of Cell Biology.

Red staining indicates the presence of activated Aurora A kinase in the epithelial cells lining cysts in the kidneys of patients with polycystic kidney disease (PKD). A new study in The Journal of Cell Biology suggests that Aurora A may contribute to PKD, a common genetic disease, by inactivating a key calcium channel in kidney cells. 

Aurora A is an oncogene best known as a regulator of mitotic progression. But the kinase has important functions during interphase as well, when it can promote cilia disassembly and can be activated by elevated calcium levels. Because both calcium signaling and cilia are defective in PKD, researchers from the Fox Chase Cancer Center in Philadelphia wondered whether Aurora A might contribute to the pathology of this common genetic disease.

The researchers found that Aurora A was up-regulated and activated in epithelial cells lining the cysts in PKD patient kidneys. In addition, Aurora A bound to and phosphorylated a calcium channel called polycystin-2, whose gene, PKD2, is often mutated in autosomal dominant forms of PKD.

Polycystin-2 mediates the release of calcium from storage in the endoplasmic reticulum and calcium influx into cilia. Inhibition or knockdown of Aurora A boosted intracellular calcium levels, but this effect was less pronounced in kidney cells lacking polycystin-2, indicating that Aurora A normally lowers calcium levels by inactivating polycystin-2. Only small doses of inhibitor were required to increase calcium levels, suggesting that Aurora A may be a viable therapeutic target for boosting polycystin-2 activity in certain PKD patients. Senior author Erica Golemis now wants to investigate how Aurora A becomes up-regulated in PKD and whether inhibitors of the kinase can slow cyst formation in mouse models of the disease.

We Are All Mutants: First Direct Whole-Genome Measure of Human Mutation Predicts 60 New Mutations in Each of Us

ScienceDaily (June 13, 2011) — Each one of us receives approximately 60 new mutations in our genome from our parents. This striking value is reported in the first-ever direct measure of new mutations coming from mother and father in whole human genomes.

Estimated numbers of new mutations in two families. Each lightning bolt represents one new mutation found in the child: mutations from Dad are in orange, from Mum in green

For the first time, researchers have been able to answer the questions: how many new mutations does a child have and did most of them come from mum or dad? The researchers measured directly the numbers of mutations in two families, using whole genome sequences from the 1000 Genomes Project. The results also reveal that human genomes, like all genomes, are changed by the forces of mutation: our DNA is altered by differences in its code from that of our parents. Mutations that occur in sperm or egg cells will be 'new' mutations not seen in our parents.

Although most of our variety comes from reshuffling of genes from our parents, new mutations are the ultimate source from which new variation is drawn. Finding new mutations is extremely technically challenging as, on average, only 1 in every 100 million letters of DNA is altered each generation.

Previous measures of the mutation rate in humans has either averaged across both sexes or measured over several generations. There has been no measure of the new mutations passed from a specific parent to a child among multiple individuals or families.

"We human geneticists have theorised that mutation rates might be different between the sexes or between people," explains Dr Matt Hurles, Senior Group Leader at the Wellcome Trust Sanger Institute, who co-led the study with scientists at Montreal and Boston, "We know now that, in some families, most mutations might arise from the mother, in others most will arise from the father. This is a surprise: many people expected that in all families most mutations would come from the father, due to the additional number of times that the genome needs to be copied to make a sperm, as opposed to an egg."

Professor Philip Awadalla,who also co-led the project and is at University of Montreal explained: "Today, we have been able to test previous theories through new developments in experimental technologies and our analytical algorithms. This has allowed us to find these new mutations, which are like very small needles in a very large haystack."

The unexpected findings came from a careful study of two families consisting of both parents and one child. The researchers looked for new mutations present in the DNA from the children that were absent from their parents' genomes. They looked at almost 6000 possible mutations in the genome sequences.

They sorted the mutations into those that occurred during the production of sperm or eggs of the parents and those that may have occurred during the life of the child: it is the mutation rate in sperm or eggs that is important in evolution. Remarkably, in one family 92 per cent of the mutations derived from the father, whereas in the other family only 36 per cent were from the father.

This fascinating result had not been anticipated, and it raises as many questions as it answers. In each case, the team looked at a single child and so cannot tell from this first study whether the variation in numbers of new mutations is the result of differences in mutation processes between parents, or differences between individual sperm and eggs within a parent.

Using the new techniques and algorithms, the team can look at more families to answer these new riddles, and address such issues as the impact of parental age and different environment exposures on rates of new mutations, which might concern any would-be parent.

Equally remarkably, the number of mutations passed on from a parent to a child varied between parents by as much as tenfold. A person with a high natural mutation rate might be at greater risk of misdiagnosis of a genetic disease because the samples used for diagnosis might contain mutations that are not present in other cells in their body: most of their cells would be unaffected.

Promising New Target for Stifling the Growth and Spread of Cancer

ScienceDaily (June 13, 2011) — Cancer and chronic inflammation are partners in peril, with the latter increasing the likelihood that malignant tumors will develop, grow and spread. Researchers at the University of California, San Diego School of Medicine say they've identified a tumor inflammation trigger that is common to most, if not all, cancers. And using existing inhibitory drugs, the scientists were able to dramatically decrease primary tumor growth in animal studies and, more importantly, halt tumor progression and metastasis.

Tumors are characterized by extensive inflammatory infiltrates, which can comprise up to 25 percent of the tumor's mass. Myeloid cells invade tumors in response to diverse inflammatory stimuli produced by the tumor. Invading myeloid cells differentiate into a type of macrophage that promotes tumor angiogenesis, growth and metastasis and inhibits anti-tumor immunity. In the June 14 issue of Cancer Cell, Schmid et al. demonstrate that tumor inflammation (myeloid cell invasion of tumors) requires PI3kinase gamma, a gatekeeper enzyme that is primarily expressed by myeloid cells. Inhibitors of PI3kinase gamma strongly inhibit tumor inflammation, growth and metastasis for a wide variety of cancers. PI3kinase gamma inhibitors hold promise as a new class of general cancer therapeutic agents.

The findings appear in the June 14 issue of the journal Cancer Cell,authored by Judith A. Varner, PhD, professor of medicine at the UC San Diego Moores Cancer Center, and colleagues in the UCSD School of Medicine and at the University of Torino, Italy.

When cancer cells appear in the body, they often provoke an immune system response. Under some circumstances, this is a good thing. But Varner and colleagues were able to show that when responding myeloid or white blood cells called macrophages are drawn to invasive cancer cells, the result can be considerable trouble for patients. Rather than suppressing the cancer, the myeloid cells are tricked by the tumor into aiding and abetting its growth and spread. Scientists have long recognized that myeloid cells can invade and promote tumor growth. But until now it was not fully appreciated how this hijacking occurs and whether there are ways to disrupt this process by suppressing the trigger that leads to myeloid cell recruitment into tumors.

Probing more deeply into the tumor inflammation process, the UCSD research team identified a range of tumor-produced molecules that attract these dangerous myeloid cells. They also pinpointed the specific trigger on myeloid cells enabling them to invade the tumor environment and accelerate tumor growth and metastasis. It is an enzyme called PI-3 kinase gamma on myeloid cells that turns on an adhesion receptor allowing the cells to enter tumors.

When researchers blocked the activity of PI-3-kinase-gamma, either genetically or through the use of a drug designed for this purpose, myeloid cells were blocked access into tumors, resulting in reduced tumor growth and a dramatic decrease in metastasis. Without the recruitment of myeloid cells, Varner said, the capability of a cancer tumor to grow is largely stifled.

"Most strategies targeting the role of myeloid cells in cancer have focused on reducing their expression of inflammatory molecules," Varner explained. "We've found a single convergent point -- the PI-3 kinase-gamma enzyme -- that, when blocked, appears to result in significant suppression of tumor inflammation and growth regardless of the initiating event. It could be a very important therapeutic target for future cancer treatments and could impact most, if not all, types of solid cancer."

Michael Karin, PhD, distinguished professor of pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction and a pioneer in inflammation research, agreed: "I think that the inhibition of PI-3K activity represents a very interesting and promising approach for inhibition of tumor-associated inflammation. It seems to fully normalize the tumor microenvironment and provide a new addition to our armamentum of anti-cancer drugs."

Varner said a number of biotechnology companies are pursuing potential drugs using PI-3-kinase inhibitors to treat diseases from cancer to heart disease to arthritis. The PI-3-kinase-gamma protein may be a particularly promising therapeutic target, because it is not widely expressed in the body, and its inhibition would likely produce fewer side effects than many therapeutics.

Funding for this research came, in part, from grants from the National Institutes of Health and the California Tobacco Related Disease Research Program.

Dengue Virus Circulating Between Monkeys and Mosquitoes Could Emerge to Cause Human Outbreaks

ScienceDaily (June 13, 2011) — More than a thousand years ago, somewhere in Southeast Asia, a fateful meeting occurred between a mosquito-borne virus that infected mainly monkeys and a large, susceptible group of humans.

The result: the world's first outbreak of dengue fever.

Today, dengue virus -- which can produce high fever, excruciating joint pain and even death -- has spread throughout tropical Asia, Africa and South America, and in 2008 it re-appeared in the Florida Keys. It could be even more widespread along the U.S. Gulf Coast but there is no surveillance in place to detect it.

Annually dengue strikes about 100 million people and causes an estimated 50,000 deaths, thriving in the urban environments infested by Aedes aegypti, the mosquito species primarily responsible for human dengue transmission.

Meanwhile, the virus' forest-dwelling counterpart -- known as "sylvatic dengue" -- continues to flourish in Southeast Asia and West Africa, cycling between non-human primates and the mosquitoes that feed on them. Since the 1970s, sylvatic dengue has received very little scientific attention -- a situation that badly needs to be remedied, according to the authors of "Fever from the forest: Prospects for the continued emergence of sylvatic dengue virus and its impact on public health," an article published online June 13 in Nature Reviews Microbiology.

"This virus continues to circulate in the forests, and now economic and ecological pressures are driving more and more people into the forests in Africa and Southeast Asia," said University of Texas Medical Branch at Galveston assistant professor Nikos Vasilakis, lead author of the paper. "In the last 10 years we've seen a number of outbreaks of disease with real public health impact caused by what we call zoonotic viruses, viruses that start out in wild animals but can also be transmitted to humans -- look at SARS, Nipah and Hendra, for example. Sylvatic dengue could be capable of a similar emergence -- or rather, re-emergence, since we know previous dengue spillovers into urban and near-urban settings have occurred."

Dengue virus may also be capable of movement from the widespread urban cycles into primates and forest mosquitoes of Latin America, which would establish a new reservoir for human infections in the New World.

In the paper, Vasilakis and his collaborators identify two factors that make a dengue re-emergence a "clear and present danger": rapid human population growth near and in tropical forests, and the fact that little or no genetic change would be needed for sylvatic dengue to adapt to human hosts and urban mosquitoes.

"Experiments show that there is little or no adaptive barrier to the emergence of sylvatic dengue into human populations," Vasilakis said. "In other words, the virus can emerge from its current environment at any time, without further adaptation."

The article also presents additional reasons for boosting research into sylvatic dengue, among them the possibility that its behavior in nonhuman primate animal models might offer critical new perspectives on the pathology of human dengue. (Most monkeys tested so far show no clinical signs of the disease, limiting their usefulness as experimental models.) Another significant issue is the possibility that vaccines against human dengue, which could be licensed in as little as five years, might push the virus to the brink of eradication in the urban, human transmission cycle, leaving an ecological opening that could be filled by sylvatic dengue.

"We see a precedent for this with yellow fever, where we have a very good vaccine -- urban yellow fever has been nearly eliminated in some regions -- but we don't have good vector control programs, and especially in South America we now have outbreaks fueled by sylvatic yellow fever," Vasilakis said. "If we eradicate human dengue and then stop vaccinating, as we often do after the disease disappears, we could see a re-emergence of dengue from a sylvatic source."

With the exception of a research program in Malaysia that ended in 1975, fieldwork on sylvatic dengue has been minimal, according to Vasilakis. In the article, he and his fellow authors call for new surveillance programs to monitor mosquitoes, non-human primates and humans in areas where sylvatic dengue is endemic, as well as the development of new diagnostic tools that will enable researchers to more easily accomplish those studies. (One such surveillance effort is now underway in Senegal, funded by the National Institutes of Health and led by UTMB professor Scott Weaver, the paper's senior author.)

"Of all the viruses with the potential to shift from animals into humans, the most likely to do so are those that, like sylvatic dengue, are carried by the non-human primates and/or bats," Vasilakis said. "For our own good, we need to know as much as we can about this virus."

Other authors of the paper include Jane Cardosa of the Universiti Sarawak Malaysia, Kathryn Hanley of New Mexico State University and Edward Holmes of Pennsylvania State University. The National Institutes of Health supported this work.