Most Mutations Come from Dad

6 09 2012

New insights into age, height and sex reshape views of human evolution

 

By R. ALAN LEO. Humans inherit more than three times as many mutations from their fathers as from their mothers, and mutation rates increase with the father’s age but not the mother’s, researchers have found in the largest study of human genetic mutations to date.

The study, based on the DNA of around 85,000 Icelanders, also calculates the rate of human mutation at high resolution, providing estimates of when human ancestors diverged from nonhuman primates. It is one of two papers published this week by the journal Nature Genetics as well as one published at Nature that shed dramatic new light on human evolution.

James Sun/Harvard Medical School

James Sun/Harvard Medical School

“Most mutations come from dad,” said David Reich, professor of genetics at Harvard Medical School and a co-leader of the study. In addition to finding 3.3 paternal germline mutations for each maternal mutation, the study also found that the mutation rate in fathers doubles from age 20 to 58 but that there is no association with age in mothers — a finding that may shed light on conditions, such as autism, that correlate with the father’s age.

The study’s first author is James Sun, a graduate student in Reich’s lab who worked with researchers from deCODE Genetics, a biopharma company based in Reykjavik, Iceland, to analyze about 2,500 short sequences of DNA taken from 85,289 Icelanders in 24,832 father-mother-child trios. The sequences, called microsatellites, vary in the number of times that they repeat, and are known to mutate at a higher rate than average places in the genome.

Reich’s team identified 2,058 mutational changes, yielding a rate of mutation that suggests human and chimpanzee ancestral populations diverged between 3.7 million and 6.6 million years ago.

A second team, also based at deCODE Genetics (but not involving HMS researchers), published a paper this week in Nature on a large-scale direct estimate of the rate of single nucleotide substitutions in human genomes (a different type of mutation process), and came to largely consistent findings.

The finding complicates theories drawn from the fossil evidence. The upper bound, 6.6 million years, is less than the published date of Sahelanthropus tchadensis, a fossil that has been interpreted to be a human ancestor since the separation of chimpanzees, but is dated to around 7 million years old. The new study suggests that this fossil may be incorrectly interpreted.

Great Heights

A second study led by HMS researchers, also published in Nature Genetics this week, adds to the picture of human evolution, describing a newly observable form of recent genetic adaptation.

The team led by Joel Hirschhorn, Concordia Professor of Pediatrics and professor of genetics at Boston Children’s Hospital and HMS, first asked why closely-related populations can have noticeably different average heights. David Reich also contributed to this study.

They examined genome-wide association data and found that average differences in height across Europe are partly due to genetic factors. They then showed that these genetic differences are the result of an evolutionary process that acts on variation in many genes at once. This type of evolution had been proposed to exist but had not previously been detected in humans.

Although recent human evolution is difficult to observe directly, some of its impact can be inferred by studying the human genome. In recent years, genetic studies have uncovered many examples where recent evolution has left a distinctive signature on the human genome. The clearest “footprints” of evolution have been seen in regions of DNA surrounding mutations that occurred fairly recently (typically in the last several thousand years) and confer an advantageous trait, such as resistance to malaria. Hirschhorn’s team observed, for the first time in humans, a different signature of recent evolution: widespread small but consistent changes at many different places in the genome, all affecting the same trait, adult height.

“This paper offers the first proof and clear example of a new kind of human evolution for a specific trait,” said Hirschhorn, who is also a senior associate member of the Broad Institute. “We provide a demonstration of how humans have been able to adapt rapidly without needing to wait for new mutations to happen, by drawing instead on the existing genetic diversity within the human population.”

Average heights can differ between populations, even populations that are genetically very similar, which suggests that human height might have been evolving differently across these populations. Hirschhorn’s team studied variants in the genome that are known to have small but consistent effects on height: people inheriting the “tall” version of these variants are known to be slightly taller on average than people inheriting the “short” versions of the same variants.

The researchers discovered that, in northern Europe, the “tall” versions of these variants are consistently a little more common than they are in southern Europe. The combined effects of the “tall” versions being more common can partly explain why northern Europeans are on average taller than southern Europeans. The researchers then showed that these slight differences have arisen as a result of evolution acting at many variants, and acting differently in northern than in southern Europe.

“This paper explains — at least in part — why some European populations, such as people from Sweden, are taller on average than others, such as people from Italy,” Hirschhorn said.

The researchers were only able to detect this signature of evolution by using the results of recent genome-wide association studies by the GIANT consortium, which identified hundreds of different genetic variants that influence height.

Funding

The Reich/deCODE study was supported by a Bioinformatics and Integrative Genomics PhD training grant (JXS), a Burroughs Wellcome Travel Grant (JXS), a Burroughs Wellcome Career Development Award in the Biomedical Sciences (DR), a HUSEC seed grant from Harvard University (DR), a SPARC award from the Broad Institute of Harvard and MIT (DR), National Science Foundation HOMINID grant 1032255 (DR), and National Institute of Health grant R01HG006399 (DR).

The Hirschhorn study was supported by the National Heart, Lung and Blood Institute’s FHS (contract no. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This work was also supported by a graduate research fellowship from the National Science Foundation (to C.W.K.C.), the March of Dimes (6-FY09-507 to J.N.H.) and the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK075787 to J.N.H.).

hms.harvard.edu [en línea] Boston (USA): hms.harvard.edu, 06 de septiembre de 2012 [ref. 23 de agosto de 2012] Disponible en Internet: http://hms.harvard.edu/content/most-mutations-come-dad



First Green, then Red – Fluorescent Dye Timer Tells the Age of Proteins

26 07 2012

In many diseases, from infections through to cancer, the protein metabolism in the cell is defective. Scientists from the German Cancer Research Center (DKFZ), the Center for Molecular Biology of Heidelberg University (ZMBH), and the European Molecular Biology Laboratory (EMBL) have now developed a method that enables them to monitor the aging process of proteins in a cell with unprecedented precision. The group has reported their results in the latest issue of Nature Biotechnology.

The novel dye timer makes visible that the mother cell keeps the older proteins (red), whereas the daughter cell forms new molecules (green).

The novel dye timer makes visible that the mother cell keeps the older proteins (red), whereas the daughter cell forms new molecules (green).

Proteins have important functions in our body: They confer structure, catalyze chemical reactions, serve as transport molecules for important substances, protect from pathogenic agents, and serve as an emergency source of energy. However, if the amount of a protein increases or decreases strongly, this often results in disease. If, for example, the p53 protein, which has been called the “guardian of the genome”, is broken down in an uncontrolled manner, processes like DNA repair, control of cell division, or induction of cell death cannot take place in the affected cell. As a result, the defective cell starts dividing uncontrollably and a tumor arises. To determine whether the protein metabolism of a cell is defective, researchers in the group of Professor Michael Knop have developed a novel method: They make proteins glow. However, instead of using a single fluorescent dye, as it is commonly done, the investigators have developed a complex of a red and a green fluorescent marker. This so-called tandem fluorescent protein timer (tFT) is linked to the protein during the very process of protein synthesis and, thus, delivers information about the amount, location and age of the molecules.

Michael Knop, leader of the Research Group “Cell Morphogenesis and Signal Transduction” in the DKFZ-ZMBH Alliance, explains how this new method works: “Immediately after the cell has formed the protein, the green dye – consisting of green fluorescent protein, GFP – starts emitting light. That means that in all those places in the cell where green light is emitted the molecule is found. Based on the color intensity of the emitted light, we are also able to determine the quantity of the protein.” From the fluorescence, the scientists are now also able to infer on the age of molecules. “As time progresses, the red fluorescent protein also starts emitting light. As a result, the proteins shift colors from green to red as they get older,” Knop continues to explain. “Thus, we can differentiate newly formed – green – proteins from old – red – ones. This enables us to calculate their lifespan and check whether a protein is being broken down more rapidly or more slowly than usual.” An additional advantage: tFTs produce very bright fluorescence so that the method has a high sensitivity.

The novel tFTs make it possible to monitor the age of proteins in a timeframe ranging from ten minutes up to several hours. If the green fluorescent protein (GFP) is combined with different fluorescent dyes, it is even possible to track breakdown processes taking place over several days. The investigators used yeast as a model organism. The reason: This single-celled organism is very similar to our cells in many basic processes and is therefore a suitable model. Moreover, Professor Elmar Schiebel, leader of the Research Group “Segregation of Chromosomes in Mitosis” in the DKFZ-ZMBH Alliance, has shown with his team that this method also works in human cells. This opens up whole new prospects for examining damaged cells and for developing new drugs to regulate protein stability in diseased cells.

Anton Khmelinskii, Philipp J Keller, Anna Bartosik, Matthias Meurer, Joseph D Barry, Balca R Mardin, Andreas Kaufmann, Susanne Trautmann, Malte Wachsmuth, Gislene Pereira, Wolfgang Huber, Elmar Schiebel & Michael Knop: Tandem fluorescent protein timers for in vivo analysis of protein dynamics. Nature Biotechnology, 2012, DOI: 10.1038/nbt.2281

 

Uni-heidelberg.de [en línea] Heidelberg (GER): uni-heidelberg.de, 26 de julio de 2012 [ref. 25 de junio de 2012] Disponible en Internet: http://www.uni-heidelberg.de/presse/meldungen/2012/m20120625_timer_en.html