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Genetic Mutations Be Beneficial

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Last Updated: 02 July 2021

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No; only a small percentage of mutations cause genetic disordersamost have no impact on health or development. For example, some mutations alter a gene's DNA sequence but do not change the function of protein made by the gene. Often, gene mutations that could cause genetic disorder are repaired by certain enzymes before a gene is expressed and an altered protein is produce. Each cell has a number of pathways through which enzymes recognize and repair errors in DNA. Because DNA can be damaged or mutate in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help individuals better adapt to changes in their or their environment. For example, beneficial mutation could result in protein that protects individuals and future generations from new strains of bacteria. Because a person's genetic code can have large number of mutations with no effect on health, diagnosing genetic conditions can be difficult. Sometimes, genes thought to be related to particular genetic condition have mutations, but whether these changes are involved in development of condition has not been determine; these genetic changes are known as variants of unknown significance or. Sometimes, no mutations are found in suspected disease - related genes, but mutations are found in other genes whose relationship to particular genetic condition is unknown. It is difficult to know whether these variants are involved in disease. The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. The National Human Genome Research Institute provides information about human genomic variation. Cold Spring Harbor National Laboratoryas DNA From Beginning explains the discovery of DNA repair mechanisms in cells and introduces researchers who work to understand these mechanisms. Force explains the significance of variants of unknown significance in cancer.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

The Unusually Well

To cure disease, researchers are starting to scour genomes of abnormally healthy. In 2009, researchers at Broad Institute in Boston, led by geneticist David Altschuler, started recruiting elderly, overweight individuals who, by all accounts, ought to have Type 2 diabetes but scientists were looking for genetic mutations that cause diabetes but rather hoping to find mutations that prevent it. Their search paid off; last year, group reported in Nature Genetics that people who have particular mutations in a gene called SLC30A8 are 65% less likely to get diabetes, even when they have risk factors like obesity. The Gene has subtle effects on insulin, and, for a fortunate few, mutations that knock out its function seem to offset forces that would, for the rest of the US, likely lead to diabetes. Similarly, protective mutationsthats disable genes but create benefits rather than problemhave been discovered somewhat accidentally in the past. One percent of Northern Europeans, for instance, are now known to carry a mutation in gene called CCR - 5 that renders cellular receptor defective and confers total immunity from HIV infection. And there is evidence of more lucky mutations lurking in human genomes, in form of people who seem to defy oddsthe long - live smokers, or individuals who remain unscathed in the midst of infectious disease outbreak. Especially intriguing are those who carry gene mutations that are known to cause disease yet who show no signs of illness. Now, cheaper sequencing is making it possible to hunt for these fairy godmother mutations and paving a more direct route toward turning discoveries into potential medications, or even targets for new gene editing techniques. It is a potentially fruitful strategy. Figuring out how to mimic effects of beneficial mutation is often simpler than determining how to reverse effects of detrimental one, says cardiologist and geneticist Sekar Kathiresan, also of the Broad Institute. The most useful genetic findings are those that decrease gene function and protect against disease, he say. These immediately tell you that if you can develop a drug that mimics mutation, it should work in humans. Finding these beneficial mutations, however, can be harder than finding disease - link DNA changes. Recruiting people who rarely use the healthcare system is one hurdle. Another is that existing genetic databases are not usually designed to identify the absence of illness. But forging ahead despite these challenges is worthwhile, says Leslie Biesecker of the National Human Genome Research Institute. Scientists have long studied single nucleotide polymorphisms that are associated with disease, and investigating opposite phenomenon will shed further light on the basic biology of how genes interact with one another, he say. Weve been studying disease cohorts for a long time, and weve learnt a lot from that. But if you really want to understand the full spectrum of the relationship between genes and disease, you have to study as many different kinds of people as you possibly can, says Biesecker.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Pathways to Therapeutics

Table

NameDiseaseMolecular DefectDonor CellAgeSex
ADAADA-SCIDGGG > AGG, exon 7 and Del(GAAGA) exon 10, ADA geneFibroblast3MMale
GDGaucher's disease type IIIAAC > AGC, exon 9, G-insertion, nucleotide 84 of cDNA, GBA geneFibroblast20YMale
DMDDuchenne muscular dystrophyDeletion of exons 45-52, dystrophin geneFibroblast6YMale
BMDBecker muscular dystrophyUnidentified mutation in dystrophin geneFibroblast38YMale
DS1Down syndromeTrisomy 21Fibroblast1Y,1MMale
PDParkinson's diseaseMultifactorialFibroblast57YMale
JDMJuvenile diabetes mellitusMultifactorialFibroblast42YFemale
SBDSShwachman-Bodian-Diamond syndromeIV2 + 2T > C and IV3 - 1G > A, SBDS geneBone marrow mesenchymal cells4MMale
HDHuntington's disease72 CAG repeats, huntingtin geneFibroblast20YFemale
LNScLesch-Nyhan syndrome (carrier)Heterozygosity of HPRT1Fibroblast34YFemale

To cure disease, researchers are starting to scour genomes of abnormally healthy. In 2009, researchers at Broad Institute in Boston, led by geneticist David Altschuler, started recruiting elderly, overweight individuals who, by ALL accounts, ought to have type 2 diabetes but scientists were looking for genetic mutations that cause diabetes but rather hoping to find mutations that prevent it. Their search paid off; last year, group reported in Nature Genetics that people who have particular mutations in a gene called SLC30A8 are 65% less likely to get diabetes, even when they have risk factors like obesity. The Gene has subtle effects on insulin, and, for a fortunate few, mutations that knock out its function seem to offset forces that would, for the rest of us, likely lead to diabetes. Similarly, protective mutationsthats disable genes but create benefits rather than problemhave been discovered somewhat accidentally in the past. One percent of Northern Europeans, for instance, are now known to carry a mutation in gene called CCR - 5 that renders cellular receptor defective and confers total immunity from HIV infection. And there is evidence of more lucky mutations lurking in human genomes, in form of people who seem to defy oddsthe long - live smokers, or individuals who remain unscathed in the midst of infectious disease outbreak.S Especially intriguing are those who carry gene mutations that are known to cause disease yet who show no signs of illness. Now, cheaper sequencing is making it possible to hunt for these fairy godmother mutations and paving a more direct route toward turning discoveries into potential medications, or even targets for new gene editing techniques. It is a potentially fruitful strategy. Figuring out how to mimic effects of beneficial mutation is often simpler than determining how to reverse effects of detrimental one, says cardiologist and geneticist Sekar Kathiresan, also of the Broad Institute. The most useful genetic findings are those that decrease gene function and protect against disease, he say. These immediately tell you that if you can develop a drug that mimics mutation, it should work in humans. Finding these beneficial mutations, however, can be harder than finding disease - link DNA changes. Recruiting people who rarely use the healthcare system is one hurdle. Another is that existing genetic databases are not usually designed to identify the absence of illness. But forging ahead despite these challenges is worthwhile, says Leslie Biesecker of the National Human Genome Research Institute. Scientists have long studied single nucleotide polymorphisms that are associated with disease, and investigating opposite phenomenon will shed further light on the basic biology of how genes interact with one another, he say. Weve been studying disease cohorts for a long time, and weve learnt a lot from that. But if you really want to understand the full spectrum of the relationship between genes and disease, you have to study as many different kinds of people as you possibly can, says Biesecker.


Introduction

Several risk factors were recognized to be associated with breast cancer development, including age, hormonal, reproductive, menstrual history, alcohol, radiation, hereditary factors, obesity, etc. Among these risk factors, age is the biggest risk factor for developing breast cancer followed by positive family history. Base on data presented in literature, previous studies discovered several features of inherited mutations in genes. It was estimated that about 10 - 30% of breast cancer cases are related to hereditary factors, also 5 - 10% of breast cancers were detected with strong hereditary factors, while between 4 and 5% of these cases were identified by mutations in high - penetrant genes. Brca1 and BRCA2 have been known as regulators of DNA repair, transcription, and cell cycle in reply to DNA damage. Brca1 and BRCA2 genes are the most commonly mutated genes that are associated with high breast cancer risk. It has been reported that 60% of hereditary breast cancers can be related to germline mutations in either of these genes. A number of genes are associated with multiple Cancer syndromes, for example phosphatase and tensin homolog protein, TP53, STK11 / LKB1, ataxia telangiectasia, and NBS1, but other genes associated with hereditary breast Cancer are emerging. Cancer predisposing genes can be classified as high - penetrant genes including BRCA2, BRCA2, TP53, STK11, and CDH1. On the other hand, majority of gens can be categorized as moderate - penetrant genes in most breast cancer cases, including CHEK2, ATM, CDH1, NBS1, BRIP1, PALB2, BARD1, RAD50, and RAD51, which are frequently mutated in the general population and contribute to the development of breast cancer. The present study tries to focus on the spectrum of mutations, polymorphisms, and variants in each gene which are linked to breast cancer as well as how it contributes to the disease.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

A Struggle Against Statistics

Wellderly, there is only one harboring potential genetic gems; examining infectious disease survivors offers another promising avenue. Wherever there is a profound infectious disease infecting the community, looking at survivors enables you to look for resistance genes which may cast enormous light on the etiology of disease and potentially lead to new treatment, says neurologist John Collinge of University College London. Researchers, for example, are investigating drugs to fight the Ebola virus that target protein known as Niemann Pick type C. Genes that encode it, when mutate, cause rare version of Niemann Pick Disease that is usually fatal in childhood to people with two copies. But in animal studies, individuals with only one mutated copy of gene resist Ebola infection because the virus needs a working version of protein to infect host cells. In other recent research, investigators have looked for gene mutations that protect against infection, or severe illness from influenza and other pathogens. In October, researchers with MalariaGEN international consortium identified a gene variant that affects blood cell surface receptor and protects against severe cases of malaria. Collinge and his colleagues have been studying survivors of more exotic epidemic: kuru, deadly neurological illness similar to Creutzfeld Jakob Disease. Like CJD, kuru is transmitted by misshapen proteins called prions, and, in the 1950s and 1960s, it spread rapidly among members of cannibalistic tribe in Papa New Guinea. When someone dies of kuru, ritualistic consumption of their body means that those participating in the ceremony would contract the disease too. In some villages, almost all women of childbearing age perish. But decades later, there were also survivorspeople who partaken in feasts and never got sick. In the early 1990s, Collinge began sequencing their genomes. Over the past two decades, hes revealed mutations in their prion protein gene, PRNP, that protect them from kuru. In those families with polymorphism, there is hardly any kuru despite very high levels of exposure, says Collinge. This year, Collinge and his colleagues report in Nature that mice with one of the mutations were protected from 18 different kinds of prion disease. This particular finding is incredibly powerful, says Collinge. We GO from 100 percent of mice dying to 0 percent. Now, researchers are working on determining the structure of protective prion proteins, which could shed light on how to mimic mutations in the rest of the human population, possibly leading to treatments for not just kuru but a variety of prion diseases. Ideally, discovery of protective mutation could inform development of drug that mimic its molecular effects in the body. Inhibitors of CETP, Study by Barzilai, have been explored as cholesterol drugs, although none has reached the market.


Gene mutations

Experts agree that it takes more than one mutation in a cell for cancer to occur. When someone has inherited an abnormal copy of a gene, though, their cells already start out with one mutation. This makes it easier for enough mutations to build up for cell to become cancer. That is why cancers that are inherited tend to occur earlier in life than cancers of the same type that are not inherit. Even if you were born with healthy genes, some of them can change over the course of your life. These acquire mutations cause most cases of cancer. Some acquire mutations can be caused by things that we are exposed to in our environment, including cigarette smoke, radiation, hormones, and diet. Other mutations have no clear cause, and seem to occur randomly as cells divide. In order for a cell to divide to make 2 new cells, it has to copy all of its DNA. With so much DNA, sometimes mistakes are made in new copy. This leads to DNA changes. Every time cells divide, there is another opportunity for mutations to occur. Numbers of gene mutations build up over time, which is why we have a higher risk of Cancer as we get older. It is important to realize that gene mutations happen in our cells all the time. Usually, cell detects change and repairs it. If it ca be repair, cell will get a signal telling it to die in a process called apoptosis. But if cell doesn't die and the mutation is not repair, it may lead to a person developing cancer. This is more likely if mutation affects gene involved with cell division or gene that normally causes defective cells to die. Some people have a high risk of developing Cancer because they have inherited mutations in certain genes. To learn more about this, see Family Cancer Syndromes.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

1. Introduction

Mutations are one of the fundamental forces of evolution because they fuel variability in populations and thus enable evolutionary change. Base on their effects on fitness, mutations can be divided into three broad categories: good or advantageous that increase fitness, bad or deleterious that decrease it and indifferent or neutral that are not affected by selection because their effects are too small. While this simplistic view serves well as the first rule of thumb for understanding the fate of mutations, research in recent decades has uncovered a complex web of interactions. For example, effects of mutations often depend on the presence or absence of other mutations, Their effects can also depend on the environment, fate of mutations may depend on the size and structure of the population, which can severely limit the ability of selection to discriminate among three types, and mutations fate can also depend on fate of others that have more pronounced effects and are in close proximity on same chromosome. A major theoretical goal in the study of population genetics of mutations is to understand how mutations change populations in the long term. To this end, we have to consider many features of evolution and extant populations at both phenotypic and molecular level, and ask how these can be explained in terms of rates and kinds of mutations and how they are affected by forces that influence their fates. We have increasing amounts of information at our disposal to help us answer these questions. Continuous improvement of DNA sequencing technology is providing more detailed genotypes on more species and observations of more phenomena at genomic level. We are also gaining more understanding of processes that lead from changes in level of genotypes through various intermediate molecular changes in individuals to new visible phenotypes. Use of this new knowledge presents both opportunities and challenges to our understanding, and new methods have been developed to address them. Brian Charlesworth has been at the forefront of many developments in population genetics of mutations, both in collection and analysis of new data and in providing new models to explain observations he and others have make. This themed issue of Phil. Trans. R. Soc. B is dedicated to him to mark his 65 birthday. Authors of accompanying papers have individually made important contributions to the field and have been directly associated with or indirectly influenced by their work. In this collection of papers, various aspects are considered in detail, and in this introduction, we aim to provide an overview as the basis for in - depth treatments that follow. We outline some of theories that serve as quantitative basis for more applied questions and have been developed with main aims of: measuring rates at which different types of mutations occur in nature, predicting quantitatively their subsequent fate in populations, and assessing how they affect some properties of populations and therefore could be use for inference.

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* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

2. Mutations

What is the distribution of mutational effects on fitness? Charlesworth once described this as the first and most difficult question he would ask the fairy godmother of evolutionary genetics. It specifies the probability distribution of selection coefficients for spontaneous mutations of give genome. Thus, it could be argued that DME is highly dependent on genotype; but all organisms are complex functional networks and have learnt to live with a flux of new mutations, such that powerful normalizing forces might cause DMEs, we can observe today, to share important properties. For example, total fitness degrading and fitness increasing effects that get fixed might be in equilibrium such that there is no unbounded change in fitness in most populations. In their paper in this issue, Keightley & Eyre - Walker show that one of the most robust findings from research on DMEs is that effects span many orders of magnitude. It is well known that some deleterious mutations are lethal while others appear to be effectively neutral in all population genetic tests, implying that heterozygous selection coefficient S of mutants ranges from 1 to more neutral than 10 7. It is hard to see why any particular range of intermediate selection coefficients should not exist, raising problems for many population genetic theories tailored towards dealing only with mutations of particular effect. Different types of mutations typically have different DMEs. For example, conservative amino acid changes usually have much smaller effects than frame - shift mutations that disfigure the rest of protein. In diploids, selection coefficients of heterozygous mutations are modulated by their dominance h. Correlation between h and S is typically strongly negative, which suggests that properties of underlying biochemical reaction networks are usually pivotal for determining dominance. Of course, not all mutations are harmful, and occasional fitness increasing mutations drive adaptive evolution. On this issue, Orr points out how some intriguing statements can be made about advantageous mutations beyond fact that they are usually rare and difficult to observe. They include back mutations that occur if a large enough number of slightly deleterious mutations were previously fix, possibly at time when effective population size was smaller, compensatory mutations that at least partially repair some harmful effects at molecular level, quantitative trait mutations that can either increase or decrease the value of trait with impact on fitness, resistance mutations that are part of biological arms races between hosts and parasites, and mutations that enable species to start expanding into new ecological niche. Frequencies and DMEs of these groups are probably very different and their predictions and estimations are likely to be fruitful fields for further research. Our knowledge of DMEs has come from laboratory experiments like that of Trindade et al. And from population genetics approaches as used by Keightley & Eyre - Walker, both of which are reported in this issue.

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* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Beyond good and bad

A study dating age of more than 1 million single - letter variations in human DNA code reveals that most of these mutations are of recent origin, evolutionarily speaking. These kinds of mutations change one nucleotide -, C, T or G - in the DNA sequence. Over 86 percent of harmful protein - coding mutations of this type arose in humans just during past 5 000 to 10 000 years. Some of the remaining mutations of this nature may have no effect on people, and few might be beneficial, according to Project researchers. While each specific mutation is rare, findings suggest that the human population acquire an abundance of these single - nucleotide genetic variants in a relatively short time. The spectrum of human diversity that exists today is vastly different than what it was only 200 to 400 generations ago, says Dr. Joshua Akey, associate professor of Genome Sciences at University of Washington in Seattle. He is one of several leaders of multi - institutional effort among evolutionary geneticists to date first appearance of a multitude of single nucleotide variants in the human population. Their findings appear in the Nov. 28 edition of Nature. The lead author is Dr. Wenqing Fu of UW Department of Genome Sciences. The work stems from collaboration among many genome scientists, medical geneticists, Molecular biologists and biostatisticians at UW, University of Michigan, Baylor College of Medicine in Houston, Broad Institute at MIT and Harvard, and Population Genetics Working Group. The study is part of the Exome Sequencing Project of National Heart, Lung, and Blood Institute at National Institutes of Health, to place this discovery in the context of prehistory and ancient history of people, humans have been around for roughly 100 000 years. In Middle East, cities form nearly 8 500 years ago, and writing was used in Mesopotamia at least 5 500 years ago. Researchers assessed the distribution of mutation ages by re - Sequencing 15 336 protein - coding genes in 6 515 people. Of them, 4 298 were of European ancestry, and 2 217 were African. Researchers base their explanation for the enormous excess of rare genetic variants in the present - day population on the Out - of - Africa model of human diaspora to other parts of the world. On average, each person has about 150 new mutations not found in either of their parents, Akey say. The number of such genetic changes introduced into population depends on its size. Larger populations, continuing to multiply by producing children, have more opportunities for new mutations to appear. The number of mutations thereby increases with accelerated population growth, such as the population explosion that began 5 115 years ago. During the Out of Africa migration of some early humans into Europe and beyond some 50 000 years ago, population bottleneck occur: number of humans plummet, and shrinking remnants become more genetically similar. Back then, mutations that were only slightly damaging had greater probability of being carried from one generation to the next, Akey explain.

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Sickle Cell

Sickle Cell Disease is a group of disorders that affect hemoglobin, molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape. Signs and symptoms of Sickle Cell Disease usually begin in early childhood. Characteristic features of this disorder include low number of red blood cells, repeat infections, and periodic episodes of pain. The severity of symptoms varies from person to person. Some people have mild symptoms, while others are frequently hospitalized for more serious complications. Signs and symptoms of Sickle Cell Disease are caused by sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to Anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. Rapid breakdown of red blood cells may also cause yellowing of eyes and skin, which are signs of jaundice. Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs, such as lungs, kidneys, spleen, and brain, of oxygen - rich blood and can lead to organ damage. A particularly serious complication of Sickle Cell Disease is high blood pressure in blood vessels that supply lungs, which can lead to heart failure. Pulmonary hypertension occurs in about 10 percent of adults with Sickle Cell Disease. Sickle Cell Disease affects millions of people worldwide. It is most common among people whose ancestors come from Africa; Mediterranean countries such as Greece, Turkey, and Italy; Arabian Peninsula; India; and Spanish - speaking regions in South America, Central America, and parts of the Caribbean. Sickle Cell Disease is the most common inherited blood disorder in the United States, affecting an estimated 100 000 Americans. The disease is estimated to occur in 1 in 500 African Americans and 1 in 1 000 to 1 400 Hispanic Americans. Mutations in HBB gene cause Sickle Cell Disease. The Hbb gene provides instructions for making one part of hemoglobin. Hemoglobin consists of four protein subunits, typically, two subunits called alpha - globin and two subunits called Beta - globin. The HBB gene provides instructions for making Beta - globin. Various versions of Beta - globin result from different mutations in the HBB gene. One particular HBB gene mutation produces an abnormal version of Beta - globin know as hemoglobin S. Other mutations in the HBB gene lead to additional abnormal versions of Beta - globin such as hemoglobin C and hemoglobin E. Hbb gene mutations can also result in unusually low levels of Beta - globin; this abnormality is called Beta thalassemia. In people with Sickle Cell Disease, at least one of the Beta - globin subunits in hemoglobin is replaced with hemoglobin S. In Sickle Cell Anemia, which is the most common form of Sickle Cell Disease, hemoglobin S replaces both Beta - globin subunits in hemoglobin. In other types of Sickle Cell Disease, just one Beta - globin subunit in hemoglobin is replaced with hemoglobin S.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

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