Did you know 
genetic Fingerprinting (also called DNA testing, DNA typing, or DNA profiling) is a technique used to distinguish between individuals of the same species using only samples of their DNA. Although two individuals will have the vast majority of their DNA sequence in common, DNA profiling exploits highly variable repeat sequences called VNTRs. These loci are variable enough that two unrelated humans are unlikely to have the same alleles. The technique was first reported in 1984 by Dr. Alec Jeffreys at the University of Leicester, and is now the basis of several national DNA identification databases.
Reference samples
DNA identification must be done by an extraction of DNA from substances such as:
Personal items (e.g. toothbrush, razor, ...)
Banked samples (e.g. banked sperm or biopsy tissue)
Blood kin (biological relative)
Human remains previously identified
Reference samples are often collected using buccal swab.
Variations of VNTR allele lengths in 6 individuals.
Did you know Genetic fingerprinting
Did you know DNA supercoil
The simple figure eight is the simplest supercoil, and is the shape a circular DNA assumes to accommodate one too many or one too few helical twists. The two lobes of the figure eight will appear rotated either clockwise or counterclockwise with respect to one another, depending on whether the helix is over or underwound. For each additional helical twist being accommodated, the lobes will show one more rotation about their axis.
The noun form "supercoil" is rarely used in the context of DNA topology. Instead, global contortions of a circular DNA, such as the rotation of the figure-eight lobes above, are referred to as writhe. The above example illustrates that twist and writhe are interconvertible. "Supercoiling" is an abstract mathematical property, and represents the sum of twist and writhe. The twist is the number of helical turns in the DNA and the writhe is the number of times the double helix crosses over on itself (these are the supercoils). The relationship of twist, writhe and supercoiling is expressed as the equation:
S = T + W.
Extra helical twists are positive and lead to positive supercoiling, while subtractive twisting causes negative supercoiling. Many topoisomerase enzymes sense supercoiling and either generate or dissipate it as they change DNA topology. DNA of most organisms is negatively supercoiled.
Do you know In part because chromosomes may be very large, segments in the middle may act as if their ends are anchored. As a result, they may be unable to distribute excess twist to the rest of the chromosome or to absorb twist to recover from underwinding--the segments may become supercoiled, in other words. In response to supercoiling, they will assume an amount of writhe, just as if their ends were joined.
Supercoiled DNA forms two structures; a plectoneme or a toroid, or a combination of both. A negatively supercoiled DNA molecule will produce either a one-start left-handed helix, the toroid, or a two-start right-handed helix with terminal loops, the plectoneme. Plectonemes are typically more common in nature, and this is the shape most bacterial plasmids will take. For larger molecules it is common for hybrid structures to form - a loop on a toroid can extend into a plectoneme. If all the loops on a toroid extend then it becomes a branch point in the plectonemic structure.
Did you know DNA Data Bank
Did you know a serial predator is on the loose in Reno, Nevada. He’s already murdered one young victim – 19-year-old Brianna Denison – and DNA evidence connects him to at least two other sexual assaults. As investigators worked to identify this monster, they ran into a huge roadblock. Detectives thought that there might be more attacks linked to the same suspect – and that the predator might be someone who lready has a criminal record. In Nevada, as in most states, every convicted felon must submit a DNA sample. But here’s the problem: in Washoe County, where Reno is located, an estimated 3000 DNA samples were sitting on a shelf, waiting to be analyzed and added to the database. Lack of funds to do all the work had created the backlog. Whether the killer’s DNA was among those 3000 samples – or if they contained evidence matching him to yet another case – the police had no way of knowing. Private citizens, unwilling to accept that, helped raise $160,000 so that the backlog could be cleared. Unfortunately, the answers police needed weren’t in there.
Even more unfortunately, the situation in Washoe County is far from unique. The Justice Department recently admitted that the FBI has a huge backlog of DNA from convicted criminals waiting to be tested – nearly 200,000 samples. And the backlog is growing. There’s no question that the FBI needs more funding for this important job, because I think that we need to expand the bureau’s nationwide DNA data bank, known as CODIS, even further. I’d like to see every state have mandatory collection of DNA from everybody charged with a felony, not just convicted of one. I’d like all of that information in CODIS, so that every law enforcement agency in the country has access to it.
Imagine if there was a national DNA data bank that was up-to-date, not years behind in its work. It would help solve hundreds of crimes – and it would help absolve many accused people of crimes they didn’t commit. We need to be uniformly collecting DNA profiles from both convicted AND accused criminals across the country. And we must make sure that everyone involved, from the FBI to local law enforcement, has all the resources they need to make that happen.
Did you know DNA Base Pairing Principle
Did you know the Base Pairing Principle is: Complementary base pairs are: adenine and thymine (A - T )guanine and cytosine (G - C)
The base pairing is called complementary because there are specific geometry requirements in the formation of hydrogen bonds between the heterocylic amines. Heterocyclic amine base pairing is an application of the hydrogen bonding principle. In the structures for the complementary base pairs given in the graphic on the left, notice that the thymine - adenine pair interacts through two hydrogen bonds represented as (T=A) and that the cytosine-guanine pair interacts through three hydrogen bonds represented as (C=G).
Although other base pairing-hydrogen bonding combinations may be possible, they are not utilized because the bond distances do not correspond to those given by the base pairs already cited. The diameter of the helix is 20 Angstroms.
Did you know alternative double-helical structures
Did you know DNA exists in many possible conformations. However, only A-DNA, B-DNA, and Z-DNA have been observed in organisms. Which conformation DNA adopts depends on the sequence of the DNA, the amount and direction of supercoiling, chemical modifications of the bases and also solution conditions, such as the concentration of metal ions and polyamines. Of these three conformations, the "B" form described above is most common under the conditions found in cells. The two alternative double-helical forms of DNA differ in their geometry and dimensions.
The A form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in enzyme-DNA complexes. Segments of DNA where the bases have been chemically-modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.
Did you know Chemical differences between DNA & RNA
Did you know both RNA and DNA are composed of repeated units. The repeating units of RNA are ribonucleotide monophosphates and of DNA are 2'-deoxyribonucleotide monophosphates.
Both RNA and DNA form long, unbranched polynucleotide chains in which different purine or pyrimidine bases are joined by N-glycosidic bonds to a repeating sugar-phosphate backbone.
The chains have a polarity. The sequence of a nucleic acid is customarily read from 5' to 3'. For example the sequence of the RNA molecule is AUGC and of the DNA molecule is ATGC
The base sequence carries the information, i.e. the sequence ATGC has different information that AGCT even though the same bases are involved.
Consequences of RNA/DNA chemistry
The DNA backbone is more stable, especially to alkaline conditions. The 2' OH on the RNA forms 2'3'phosphodiester intermediates under basic conditions which breaks down to a mix of 2' and 3' nucleoside monophosphates. Therefore, the RNA polynucleotide is unstable.
The 2' deoxyribose allows the sugar to assume a lower energy conformation in the backbone. This helps to increase the stability of DNA polynucleotides. The following link shows 3-D models of the DNA and RNA nucleotides.
Cytidine deamination to Uridine can be detected in DNA but not RNA because deamination of Cytidine in DNA leads to Uridine not Thymidine. Uridine bases in DNA are removed by a specific set of DNA repair enzymes and replaced with cytidine bases.
Do you know
Live is DNA
As fans of the “CSI” television shows know, DNA testing is an amazing tool for solving crimes. That said, the potential benefits of RNA / DNA’s ability to enhance and preserve the crime of aging makes it the most advance dynamic formula on the market today. Full Spectrum RNA/DNA HGH with IGF-1 and GHRH not only incorporates all of the elements of HBC’s renound Full Spectrum Growth Hormone Formula, but it now has recombinant DNA and RNA in multiple potencies for a broad range of activity. It will support and rapidly encourage Growth Hormone release, production, assimilation as it renews and replenishs overrall health faster than any Growth Hormone formulation on the market today.
In the body, RNA helps to transfer genetic messages from the DNA to guide the manufacture of proteins using the amino acids that are extracted from foods or created by the body. What this means in practical terms for medicine is that the RNA has the ability to direct the synthesis of proteins. This is an amazingly powerful concept. It doesn’t matter if the proteins are involved in heart disease, cholesterol metabolism, or weight management. By modulating the levels of RNA one has the ability to specifically affect the levels of any protein in the body in a specific way. This process of modifying the RNA to make changes in the protein is a naturally occurring regulatory process. This natural process of RNA regulation is used by bacteria, plants, and animals as a central regulatory system. For instance, when your body is exposed to heat, your body responds by making a group of proteins called heat shock, or stress activated proteins. The way that your body translates the information to make these proteins after the body has sensed heat, or stress is by modifying the levels of specific RNAs that are necessary to direct the synthesis of the specific proteins. The way that your body is able to respond to environmental changes is by modifying the RNA levels so that different proteins can be made in response to a situation.
Cloning DNA
The word "clone" has several different meanings in biology. As a noun, a clone is an identical genetic copy of either a piece of deoxyribonucleic acid (DNA), a cell, or a whole organism. Identical twins are clones, as are two daughter cells produced by mitosis. As a verb, "to clone" means to produce identical genetic copies of either pieces of DNA, cells, or whole organisms.
Large quantities of identical DNA can be produced via the polymerase chain reaction (PCR), but only if the DNA pieces are rather short (less than about 40 kilobases [kb], and usually closer to 1 kb). For larger pieces, or for protein production, DNA is almost always cloned in bacteria.
• Isolate and purify all the DNA from a sample of human cells. Break apart the cells and then wash, centrifuge, and use other purification techniques.
• Cut the DNA into millions of small fragments using restriction enzymes. Each DNA piece may be as large as 10 kb, but is more commonly 1 to 5 kb.
• Mix the DNA fragments with plasmids that have been cut with the same restriction enzymes. Add DNA ligase, an enzyme that joins the human DNA fragments to the plasmids and seals the circles up again. By using the right ratio of plasmid to fragment, a researcher can ensure that each plasmid harbors at most one human DNA fragment. With luck, one DNA fragment will contain the insulin gene.
• Cause a bacterial culture to take up the plasmids. This can be done by ionic shock. Again, adjusting the ratio can ensure one plasmid per bacterium. The plasmid used usually carries a gene for antibiotic resistance.
• Grow the bacteria on antibiotic-containing agar plates, spread very thinly. The antibiotic will kill bacteria that didn't take up the plasmid. Single bacteria give rise to colonies, which will appear as small spots on the plate. The resulting bacterial colonies are called a genomic library.
• To find which of the colonies includes the human insulin gene, use a probe. This is typically a radioactive segment of DNA whose sequence is complementary to part of the insulin gene, allowing it to bind. Apply the probe, and see where it sticks.
• Isolate that colony, and let it multiply in a rich broth. Each bacterium will replicate the insulin gene, providing many copies to work with. Including the appropriate promoters and other regulatory factors will prompt the bacteria to synthesize the human insulin protein, which can then be purified for medical use.
Several modifications of this technique allow cloning of even larger DNA fragments. Cloning into the bacterial virus bacteriophage λ allows use of fragments up to about 20 kb. In this scheme, the bacteriophage infects cultured bacteria and directs production of the gene of interest. Cosmid vectors can package about 44 kb. These are plasmids containing special sequences from bacteriophage (λ) that promote very efficient sealing of the plasmid circle. Bacterial artificial chromosomes (BACs) can contain up to 300 kb, and yeast artificial chromosomes (YACs), grown in yeast cells, can handle up to 2,000 kb, or 2 megabases.
Cloning an Animal
Since the nucleus of virtually every animal cell contains the entire genome of the animal, it might seem easy enough to clone an animal by placing the nucleus in an egg cell from which the nucleus has been removed. While this was tried many times, it was never successfully accomplished until 1996, in the creation of the sheep Dolly by Ian Wilmut and colleagues in Scotland. Dolly was the first mammal created using the nucleus from a cell of a mature adult mammal. Prior to this feat, it had been thought that normal mammalian development caused irreversible changes in some portion of the DNA that prevented it from acting as embryonic DNA does.
Amphibians have long been cloned from adult cells, but they invariably die in the tadpole stage. Adult amphibians, though, have been successfully cloned for many years from embryo nuclei. In this technique, nuclei from cells of an early embryo are extracted using a very fine glass pipette and placed in egg cells that have been shed by a female amphibian such as a frog (after removing the unfertilized egg cell nucleus). In 1998, mice were cloned from adult somatic cell nuclei, using the same technique as was used for Dolly. This technique may become especially important for producing large numbers of transgenic animals, for use in research or production of specialized proteins. However, cloned mammals are generally not very healthy. Apparently development is not quite normal when it begins with a nucleus that has already existed in another animal, compared to a genome derived from a sperm and an egg.
Damage To Sperm DNA Affects Older Men's Chances Of Fathering Children
Do you know Dr. Sergey Moskovtsev, of the Mount Sinai Hospital, Toronto, Canada, told the conference that an increase in the average maternal and paternal ages at the time of attempted first pregnancy made this particularly significant. "Older men tend to reproduce with older women", he said, "and the combination of increased female factor infertility, increased sperm DNA damage, low levels of DNA repair, and increased abnormalities in conventional semen parameters present in this population will have a pronounced impact on their reproductive potential."
Do you know Dr. Moskovtsev and his team examined the relationship of DNA integrity, a novel semen parameter related to fertility potential, to age in 2134 men presenting for evaluation of their fertility. They identified damaged and normal sperm by means of a fluorescent dye that attaches to DNA, staining red when attached to damaged DNA and green to normal. Using 20 000 sperm per sample, they calculated DNA damage in each specimen via the ratio of red to green plus red. They found that DNA damage was significantly higher in men over 45 years old than in all younger age groups, and that the damage was doubled in those men 45 years and older compared with those less than 30 years old.
"Sperm DNA damage cannot be repaired", said Dr. Moskovtsev, "and appears to be a marker of reduced fertility potential rather than a predictor of fertility. Men with normal DNA integrity may be infertile for various reasons. We need to investigate the possibility of developing techniques to identify and select sperm without DNA damage for use in assisted reproduction techniques." IVF and ICSI cannot overcome abnormalities in DNA integrity, said Dr. Moskovtsev, who intends to follow up his work by investigating further the role of abnormalities in protamine, a protein found in sperm. This is one of the putative causes of reduced DNA integrity in sperm. He will also look at older and younger groups of men with abnormal DNA integrity to see if there are differences in the mechanism of DNA damage between the two groups.
"The effect of age on male fertility is particularly interesting because of the growth in the number of men choosing to father children at older ages", he said. "In the United States, the birth rate for fathers older than 35 years increased by almost 20% between 1980 and 1995. ESHRE has reported that there had been an increase in the number of men between 50 and 65 years of age attending andrology centres over the same time period, and our study confirms these observations -- men over 40 made up almost 25% of our patient population.
"Many of these older couples will have trouble in conceiving and resort to IVF and ICSI", he said. "This will bypass the natural selection of normal, healthy sperm and may lead to fertilisation by sperm with damaged DNA which can result in early embryonic loss or the birth of unhealthy offspring."
An assessment of DNA damage in sperm should be an essential part of any examination of the fertility potential of older men, he said.
DNA damage in infertile men's sperm
The sperm of infertile men may look and behave normally, but have hidden genetic damage that could stop them producing a child.
Approximately half of all infertility is thought to be due to problems on the man's side.
However, the precise mechanism of many of these cases remains unexplained.
A team of researchers from Cleveland, Ohio in the US looked at the sperm of 92 men undergoing fertility treatment and compared it with the sperm of 16 fertile men.
Many of the infertile men had obviously defective sperm, either abnormal-looking or unable to swim normally.
However, 25% of the infertile men had normal-looking sperm.
All the sperm were genetically tested to look for signs of damaged DNA in their genetic structure.
DNA problems
As expected, the abnormal sperm had a high rate of DNA damage.
But just under half the men with normal-appearing sperm also had signs of this damage.
The finding is a concern because of pre-existing fears that a particular fertility technique might be passing genetic defects from infertile fathers to their children.
Normal in-vitro fertilisation (IVF) involves simply putting millions of sperm and a number of eggs in a dish together and hoping the sperm will perform their usual function of swimming up to the egg, penetrating its surface and triggering cell division into an embryo.
However, where sperm are few, or poor swimmers, or where IVF has failed to work, a technique called intra-cytoplasmic sperm injection (Icsi) is used.
In this, a single sperm is selected by lab workers and physically injected into the egg.
Defects
Studies have suggested a higher rate of infertility-linked birth defects among Icsi-conceived babies, and there are concerns that babies born under these circumstances will be more likely to be infertile themselves.
There are also concerns that Icsi babies might be more prone to cancer - but there is no study evidence so far to back this up.
The latest research supports those fears, by highlighting the high level of DNA damage in the sperm.
Dr Ramadan Saleh, who authored the paper in the journal Fertility and Sterility, said: "Icsi is the technique used primarily for the treatment of infertile men with very poor sperm quality.
"The use of DNA-damaged sperm to fertilise the egg may have adverse consequences such as fertilisation failure, early embryo death, miscarriage, childhood cancer and infertility in the offspring."
He suggested that infertile men might be better spotted using DNA damage analysis of their sperm rather than simply examining its physical appearance.
DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites
BACKGROUND: The ubiquitous use of phthalate esters in plastics, personal care products and food packaging materials results in widespread general population exposure. In this report, we extend our preliminary study on the relationship between urinary concentrations of phthalate metabolites and sperm DNA damage among a larger sample of men and include measurements of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), two oxidative metabolites of di-(2-ethylhexyl) phthalate (DEHP). METHODS: Among 379 men from an infertility clinic, urinary concentrations of phthalate metabolites were measured using isotope-dilution high-performance liquid chromatography-tandem mass spectrometry. Sperm DNA damage measurements, assessed with the neutral comet assay, included comet extent (CE), percentage of DNA in tail (Tail%) and tail distributed moment (TDM). RESULTS: Monoethyl phthalate (MEP), a metabolite of diethyl phthalate, was associated with increased DNA damage, confirming our previous findings. Mono-(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP, was associated with DNA damage after adjustment for the oxidative DEHP metabolites. After adjustment for MEHHP, for an interquartile range increase in urinary MEHP, CE increased 17.3% [95% confidence interval (CI) = 8.7-25.7%], TDM increased 14.3% (95% CI = 6.8-21.7%) and Tail% increased 17.5% (95% CI = 3.5-31.5%). CONCLUSIONS: Sperm DNA damage was associated with MEP and with MEHP after adjusting for DEHP oxidative metabolites, which may serve as phenotypic markers of DEHP metabolism to ‘less toxic’ metabolites. The urinary levels of phthalate metabolites among these men were similar to those reported for the US general population, suggesting that exposure to some phthalates may affect the population distribution of sperm DNA damage.
Oxidative Stress/DNA Damage and DNA Repair
Oxidative stress is produced in cells by oxygen-derived species resulting from cellular metabolism and from interaction with cells of exogenous sources such as carcinogenic compounds, redox-cycling drugs and ionizing radiations. DNA damage caused by oxygen-derived species including free radicals is the most frequent type encountered by aerobic cells. DNA damage caused by oxygen-derived species including free radicals is the most frequent type encountered by aerobic cells. When this type of damage occurs to DNA, it is called oxidative DNA damage and it can produce a multiplicity of modifications in DNA including base and sugar lesions, strand breaks, DNA-protein cross-links and base-free sites. Accurate measurement of these modifications is essential for understanding of mechanisms of oxidative DNA damage and its biological effects. Numerous DNA lesions have been identified in cells and tissues at steady-state levels and upon exposure to free radical-generating systems. Data accumulated over many years clearly show that oxidative DNA damage plays an important role in a number of disease processes. Thus, oxidative DNA damage is implicated in carcinogenesis and neurodegenerative diseases such as Alzheimer’s disease. There is also strong evidence for the role of this type of DNA damage in the aging process. The accumulation of oxidative DNA damage in non-dividing cells is thought to contribute to age-associated diseases. DNA damage is countered in cells by DNA repair, which is a basic and universal process to protect the genetic integrity of organisms. The genomes of organisms encode DNA repair enzymes that continuously monitor chromosomes to correct DNA damage. Multiple processes such as base- and nucleotide-excision pathways exist to repair the wide range of DNA damages. If left unrepaired, oxidative DNA damage can lead to detrimental biological consequences in organisms, including cell death, mutations and transformation of cells to malignant cells. Therefore, DNA repair is regarded as one of the essential events in all life forms. There is an increasing awareness of the importance of oxidative DNA damage and its repair to human health. Thus, it becomes exceedingly important to understand, at the fundamental level, the mechanisms of oxidative DNA damage, and its processing by DNA repair enzymes as well as how unrepaired DNA lesions may lead to cytotoxicity, mutagenesis and eventually to diseases and aging. More detailed knowledge of mechanisms of DNA damage and repair might allow us to modulate DNA repair. This could lead to drug developments and clinical applications including the improvement of cancer therapy by inhibiting DNA repair in drug- or radiation-resistant tumors and/or the increase in the resistance of normal cells to DNA damage by over-expressing DNA repair genes.
Watercress Reduce DNA Damages Leading to Cancer
According to a study published in this month’s American Journal of Clinical Nutrition, a watercress diet resulted to
significant reduction in DNA damage to lymphocytes (white blood cells), by 22.9 per cent.
reduction in DNA damage to lymphocytes (white blood cells) when a sample was challenged with the free radical generating chemical hydrogen peroxide, by 9.4%
reduction in blood triglyceride levels, by an average of 10%
significant increase in blood levels of lutein and beta-carotene, which have antioxidant activity, by 100% and 33% respectively (higher intakes of lutein have also been associated with a lower incidence of eye diseases such as cataract and age-related macular degeneration).
Repair of clustered uracil DNA damages in Escherichia coli
Multiply damaged sites (MDS) are defined as greater than/equal to two lesions within 10–15 bp and are generated in DNA by ionizing radiation. In vitro repair of closely opposed base damages =" src="http://nar.oxfordjournals.org/math/ge.gif" border=0>2 bp apart results in a double strand break (DSB). This work extends the in vitro studies by utilizing clusters of uracil DNA damage as model lesions to determine whether MDS are converted to DSBs in bacteria. Lesions were positioned within the firefly luciferase coding region, transformed into bacteria (wild-type, uracil DNA glycosylase-deficient, ung–, or exonuclease III and endonuclease IV-deficient, xth–nfo–) and luciferase activity measured following repair. DSB formation was expected to decrease activity. Two closely opposed uracils separated by 7 bp decreased luciferase activity in wild-type and xth–nfo–, but not ung– bacteria. Growth of bacteria to obtain plasmid-containing colonies demonstrated that the plasmid was destroyed following the mis-repair of two uracils positioned 7 bp apart. This study indicates a DSB is formed when uracil DNA glycosylase initiates repair of two closely opposed uracils 7 bp apart, even in the absence of the major apurinic endonucleases. This work supports the in vitro studies and demonstrates that DNA repair is not always advantageous to cells.
Diabetes Damages DNA In Men's Sperm And May Affect Fertility
Scientists have found that sperm from diabetic men have greater levels of DNA damage than sperm from men who do not have the disease. They warn that such DNA damage might affect a man's fertility. In the first study [1] to compare the quality of DNA in sperm from diabetic and non-diabetic men, the researchers from Belfast, Northern Ireland showed that the DNA in the nuclei of the sperm cells had greater levels of fragmentation in diabetic men (52%, versus 32% in non-diabetic men), and that there were more deletions of DNA in the tiny, energy-generating structures in the cells called mitochondria (4 versus 3). Dr Ishola Agbaje, who undertook the research published online today (Thursday 3 May) in the journal Human Reproduction, said: "As far as we know, this is the first report of the quality of DNA in the nucleus and mitochondria of sperm in diabetes. Our study identifies important evidence of increased DNA fragmentation of nuclear DNA and mitochondrial DNA deletions in sperm from diabetic men. These findings cause concern, as they may have implications for fertility." The incidence of type 1 and type 2 diabetes is increasing rapidly worldwide. While diet and obesity are known to be key factors in the increase of type 2 (or late onset) diabetes, type 1 diabetes which is usually diagnosed in childhood or adolescence, is increasing by three per cent a year in European children, although the reason for this is not entirely clear. Genetic factors that make people more susceptible, or environmental factors such as viruses that may trigger the onset of type 1 diabetes, could play a role. Dr Agbaje, a research fellow in the Reproductive Medicine Research Group at Queen's University, Belfast, said: "If the increasing trend in the incidence of type I diabetes continues, this will result in a 50% increase over the next ten years. As a consequence, diabetes will affect many more men prior to and during their reproductive years. Infertility is already a major health problem in both the developed and developing world, with up to one in six couples requiring specialist investigation or treatment in order to conceive. Moreover, the last 50 years have seen an apparent decline in semen quality. Sperm disorders are thought to cause or contribute to infertility in 40-50% of infertile couples. The increasing incidence of systemic diseases such as diabetes may further exacerbate this decline in male fertility. However, it is not clear to what extent clinics consider information about the diabetic status of their patients when investigating fertility problems." [2] Dr Agbaje and his colleagues examined sperm from 27 diabetic men, with an average age of 34, and 29 non-diabetic men with an average age of 33. They found that although semen volume was significantly less in diabetic men (2.6 versus 3.3 ml), there were no significant differences in sperm concentration, total sperm output, form and structure of the sperm or their ability to move. When they measured DNA damage they found that the percentage of fragmented nuclear DNA was significantly higher in sperm from the diabetic men and that the number of deletions in mitochondrial DNA was also higher - the number of deletions ranged from three to six (average four) in the diabetic men and from one to four (average three) in the non-diabetic men. Professor Sheena Lewis, scientific director of the Reproductive Medicine Research Group, said: "Our study shows increased levels of sperm DNA damage in diabetic men. From a clinical perspective this is important, particularly given the overwhelming evidence that sperm DNA damage impairs male fertility and reproductive health. Other studies have already shown that, while the female egg has a limited ability to repair damaged sperm DNA, fragmentation beyond this threshold may result in increased rates of embryonic failure and pregnancy loss. In the context of spontaneous conception, sperm DNA quality has been found to be poorer in couples with a history of miscarriages." However, Prof Lewis said that it was not possible to say from this current study whether the DNA damage caused by diabetes would have the same effect on men's fertility and the health of future children as DNA damage caused by other factors such as smoking. "This is just one, relatively small study that highlights a possible concern. Further studies need to be carried out in order to understand the precise nature of the diabetes-related damage, the causal mechanisms and the clinical significance. Given the global rise in the prevalence of diabetes, it is also vital to examine the reproductive outcomes of pregnancies fathered by diabetic men, and the prevalence of diabetes amongst men attending for infertility treatment," she concluded.----------------------------Article adapted by Medical News Today from original press release.---------------------------- [1] Insulin dependent diabetes mellitus: implications for male reproductive function. Human Reproduction. doi:10.1093/humrep/dem077. [2] Studies have estimated the prevalence of diabetes in sub-fertile men as 1% - three times more than expected (0.3%), given the prevalence of diabetes and male infertility in the general population. This suggests that diabetes is having a significant impact on male fertility.
DNA Repair
Damage can occur to all cellular molecules. If RNAs or proteins are damaged, they can be degraded and newly synthesized via transcription and translation using DNA as the template (later).
However, because DNA is the genetic material, changes in its structure can result in mutations (in the change of the base sequence). Although mutations can sometimes be beneficial, the overwhelming majority is not.
Mutations in DNA can result from incorporation of incorrect bases during replication or DNA may undergo chemical changes either spontaneously (Fig. 12.23) or as a result of exposure to chemicals (Fig. 12.22) or radiation (Fig. 12.28).
As we will see, some chemical changes occur with an extraordinary frequency. The resulting huge frequency of mutations would be devastating for the survival of the cell and overwhelm any beneficial mutation that might have ocurred among them.
Cells had to evolve mechanisms to repair damaged DNA:
Classes of repair mechanisms:
1) direct reversal of damage reaction 2) removal of damaged bases and replacement with newly synthesized DNAAlso, mechanisms to cope with damage if it cannot be repaired.
Direct reversal:
Only a few types of damage are repaired in this way although it is probably the most energy efficient. Especially the formation of pyrimidine dimers, which is the major type of damage induced by UV light. Pyrimidine dimers are formed between adjacent pyrimidines (particularly thymines) on the same strand of DNA by the formation of a cyclobutane ring resulting from saturation of the double bonds in their ring structure (Fig. 12.25).
Pyrimidine dimers distort the double helical structure of DNA and block transcription or replication past the damaged site. Recognition of distortions in the double helix is the major way that DNA damage is generally recognized in the cell.
One mechanism of repair (there are several others) is through direct reversal of the dimerization reaction. The process is called photoreactivation because the energy to break the cyclobutane ring is derived from visible light. Therefore, in this kind of repair mechanism the original pyrimidine bases are restored and remain in the DNA.
The repair of pyrimidine dimers by photoreactivation by the enzyme photolyase, is common to many prokaryotes and eukaryotes (E. coli, yeast, and several species of plants and animals). However, photoreactivation is not universal. Many species (including humans) lack this kind of repair mechanism. But humans have other kinds of repair mechanisms that directly reverse certain damages.
Excision repair (movie)
Most important repair mechanism. Damaged DNA is recognized, removed either as free bases or as nucleotides, and the gap is filled by synthesis of new DNA using the complementary strand as a template (Fig. 12.26).
Types of excision repair: 1) base excision repair 2) nucleotide excision repair 3) mismatch repair
One example for base excision repair is the removal of uracil from DNA. Most uracil in DNA arises from the deamination of cytosine which directly leads to the structure of uracil (Fig. 12.23).
In humans it occurs at a frequency of about 100 times a day in each cell.
If uracil is not repaired, it will base pair with adenine during the next round of replication and thus cause a mutation. The general use of thymine instead of uracil in DNA allows the repair system to recognize deaminated cytosine as incorrect.
In general, the excision of a base is catalyzed by DNA glycosylase, which cleaves the bond between the base and the deoxyribose (called glycosidic bond). The result is an apyrimidinic or apurinic (AP) site: a sugar with no base attached.
AP sites also form through spontaneous loss of a base. This occurs especially often with purines, for example several thousand times a day in a human cell.
Repair of AP sites by AP endonuclease: cleaves adjacent to AP site.
The deoxyribose is removed and the single base gap filled by DNA polymerase and ligase.
Nucleotide excision repair removes a whole oligonucleotide that containes the damage. Thymine-thymine dimer residues are examples of damage caused by UV radiation (Fig. 12.25).
In E. coli three genes involved (uvrA, B and C). The protein UvrA recognizes the damage, recruits UvrB and UvrC which cleave at 3' and 5' site of damage, respectively, producing an oligonucleotide of 12 or 13 bases.
Helicase necessary to remove oligonucleotide (disruption of hydrogen bonds from base pairing), DNA polymerase fills gap, ligase seals.
Nucleotide excision repair also in eukaryotes. Similar mechanism. Mismatch repair system (movie)
Recognizes mismatches resulting from replication. Scans newly replicated DNA, identifies mismatch, excises the mismatched base specifically from new strand so error can be repaired (Fig. 12.24).
How can the old strand of DNA be distinguished from the new strand after replication?
In E. coli, because new strand not yet methylated at GATC sequences as is normally the case (A of GATC methylated).
In E. coli mismatch repair is initiated by the protein MutS, which recognizes mismatch, and forms complex with MutL and MutH. Then MutH (an endonuclease) cleaves the unmethylated DNA strand at a GATC sequence.
Eukaryotes have a similar mismatch repair system, but the mechanism by which they identify the newly replicated DNA strand is not known.
If DNA contains damaged bases (like a pyrimidine dimer) that cannot be repaired, replication and transcription are blocked at this site. However, there are mechanisms to circumvent the damaged site. For example, replication can be initiated downstream of the damaged site by an Okazaki fragment. The result is a gap in the new daughter strand opposite the damage of the parental strand. Recombinational repair (Repair mechanisms for gaps) (movie)
Recombinational repair makes use of the undamaged parental strand to undergo recombination shifting the gap to the other newly synthesized DNA molecule, the one that does not contain the damage. Because the gap is now opposite an undamaged strand, it can be filled by DNA polymerase. And the damage lies now opposite a normal strand and can be dealt with later. SOS repair, Error-prone repair (movie)
In error-prone repair, the gap opposite the site of DNA damage is directly filled by newly synthesized DNA. But because of damage to the template the repair is very inacurate and leads to frequent mutations. Error-prone repair is used only in bacteria that have been subjected to potentially lethal conditions (such as extensive UV irradiation), where damage is so enormous that cell death is probably the only alternative.
DNA Molecule - Two Views
DNA Molecule - Two Views
Legend:
The double helix of the DNA is shown along with details of how the bases, sugars and phosphates connect to form the structure of the molecule.
DNA is a double-stranded molecule twisted into a helix (think of a spiral staircase). Each spiraling strand, comprised of a sugar-phosphate backbone and attached bases, is connected to a complementary strand by non-covalent hydrogen bonding between paired bases. The bases are adenine (A), thymine (T), cytosine (C) and guanine (G). A and T are connected by two hydrogen bonds. G and C are connected by three hydrogen bonds.
Structure of DNA
The structure of DNA is illustrated by a right handed double helix, with about 10 nucleotide pairs per helical turn. Each spiral strand, composed of a sugar phosphate backbone and attached bases, is connected to a complementary strand by hydrogen bonding (non- covalent) between paired bases, adenine (A) with thymine (T) and guanine (G) with cytosine (C). Adenine and thymine are connected by two hydrogen bonds (non-covalent) while guanine and cytosine are connected by three.
This structure was first described by James Watson and Francis Crick in 1953.
What is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences.
DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.
An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.
dna molecule:Genes
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DNA RNA REPLICATION. difference between dna rna
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DNA, RNA and Protein Synthesis
DNA molecules are incredibly long, but also very thin. One DNA molecule from the chromosome of a mammal may be about 1 m long when unraveled. However, it has to fit in a nucleus of some 5-6 orders of magnitude smaller and is folded up in chromosomes in a highly organized manner. DNA is a linear polymer that is composed of four different building blocks, the nucleotides. It is in the sequence of the nucleotides in the polymers where the genetic information carried by chromosomes is located. Each nucleotide is composed of three parts: (1) a nitrogenous base known as purine (adenine (A) and guanine (G)) or pyrimidine (cytosine (C) and thymine (T)); (2) a sugar, deoxyribose; and (3) a phosphate group (see pp. 20-22 of Molecular Biotechnology for molecular structures of DNA and its components). The nitrogenous base determines the identity of the nucleotide, and individual nucleotides are often referred to by their base (A, C, G, or T). One DNA strand can be up to several hundred million nucleotides in length. T can form a hydrogen bond with A, and C with G; two DNA strands wind together in an antiparallel fashion in a double-helix.
Inside the cell, the DNA acts like an "instruction manual": in its sequence, it provides all the information needed to function, but the actual work of translating the information into a medium that can be used directly by the cell is done by RNA, ribonucleic acid. The structural difference with DNA is that RNA contains a -OH group both at the 2' and 3' position of the ribose ring, whereas DNA (which stands, in fact, for deoxy-RNA) lacks such a hydroxy group at the 2' position of the ribose. See http://www.ch.cam.ac.uk/magnus/molecules/nucleic/sugars.html. The same bases can be attached to the ribose group in RNA as occur in DNA, with the exception that in RNA thymine does not occur, and is replaced by uracil, which has an H-group instead of a methyl group at the C-5 position of the pyrimidine. The molecular structures of uracil and thymine are compared at http://www.ch.cam.ac.uk/magnus/molecules/nucleic/bases.html. The RNA has three functions: (a) it serves as the messenger that tells the cell (the ribosomes) what protein to make (messenger RNA; mRNA); (b) it serves as part of the structure of the ribosome, the protein/RNA complex that synthesizes proteins according to the information presented by the mRNA (ribosomal RNA; rRNA); and (c) it functions to bring amino acids (the constituents of the proteins) to the ribosome when a specific amino acid "is called for" by the information on the mRNA to be put in into the protein that is being synthesized; this RNA is called transfer RNA (tRNA).
An important point of emphasis should be that all vegetative cells of one organism contain the same genetic information. Upon division, each daughter cell obtains an "exact" copy of the DNA of the parent (see http://accessexcellence.org/AB/GG/dna_replicating.html). However, the specific genes that are expressed at specific times may be very different between different tissues. These differences in gene expression allow for the regulation of development of the organism, and for the development of different tissues. For the most part, DNA-binding proteins (encoded by the DNA) play an important role in the regulation of expression of genes encoded on the DNA. A very important "chicken-and-egg" problem.....
RNAs
The messenger RNA (mRNA) serves as an intermediate between DNA and protein. Parts of the DNA are "transcribed" into transcripts (single-stranded RNA molecules) that are processed to mRNA. In prokaryotes the transcript generally does not need to be processed, and can serve as mRNA right away. Transcription starts at a specific site on the DNA called a promoter. Each gene or operon has its own promoter(s). Transcription ends at a terminator sequence on the DNA. The transcripts usually are 300-50,000 nucleotides long, and contain the information to make protein. In eukaryotes (organisms with cells containing a nucleus; in fact, any higher organism) generally the transcripts needs to be processed before they can serve as a blueprint for a protein. The processing involves the removal of intervening sequences (introns) in the gene. The introns may be anywhere between 50 and 10,000 nucleotides in length. The coding regions of the mRNA are called exons. There may be up to 100 introns in a single gene. The introns are spliced out by small ribonucleoprotein particles (consisting of RNA and protein), which appear to pull the two ends of the intron together. However, there are also introns that splice out without the need of a protein: the RNA sequence itself appears to contain sufficient information to know where to splice out the intron. In addition to the removal of introns, a poly-A sequence is added to the 3’ end of the transcript. The processed transcript is the mRNA, and the information in the mRNA can be used to be "translated" into a protein of specific sequence. However, in prokaryotes introns are rare and mRNA generally does not get processed before translation.
The intron splicing process provides an opportunity to increase the amount of usable genetic information without increasing the genome size of the organism: Alternative splicing of a particular transcript can occur. Alternative splicing means that introns may be recognized in different ways in different molecules of the same primary transcript, and the result is that one gene can give rise to different mRNAs and thereby to different proteins. Note that this process is largely limited to eukaryotes as introns in prokaryotes are rare.
Ribosomal RNAs (rRNAs) are essential components of an important part of the protein synthesis machinery: the ribosomes. In addition to rRNA, there are some 70 different proteins in a ribosome. There are hundreds of copies of rRNA genes per genome, thus making the production of lots of rRNA possible. There are four different rRNAs, each with a different size. Each ribosome contains one molecule of each of the four rRNA types. In prokaryotes, ribosomes bind to the mRNA close to the translation start site. This ribosome binding site is referred to as the Shine-Dalgarno sequence or as the ribosome recognition element. In eukaryotes, ribosomes bind at the 5' end of the mRNA and scan down the mRNA until they encounter a suitable start codon.
Transfer RNA (tRNA) carries amino acids to the ribosomes, to enable the ribosomes to put this amino acid on the protein that is being synthesized as an elongating chain of amino acid residues, using the information on the mRNA to "know" which amino acid should be put on next. For each kind of amino acid, there is a specific tRNA that will recognize the amino acid and transport it to the protein that is being synthesized, and tag it on to the protein once the information on the mRNA calls for it.
All tRNAs have the same general shape, sort of resembling a clover leaf. Parts of the molecule fold back in characteristic loops, which are held in shape by nucleotide-pairing between different areas of the molecule. There are two parts of the tRNA that are of particular importance: the aminoacyl attachment site and the anticodon. The aminoacyl attachment site is the site at which the amino acid is attached to the tRNA molecule. Each type of tRNA specifically binds only one type of amino acid. The anticodon (three bases) of the tRNA base-pairs with the appropriate mRNA codon at the mRNA-ribosome complex. This temporarily binds the tRNA to the mRNA, allowing the amino acid carried by the tRNA to be incorporated into the polypeptide in its proper place. Thus, the sequence of the codon (three bases) in the mRNA dictates the amino acid to be put in in the protein at a specific site. The "dictionary" of codons coding for amino acids is called the genetic code. A summary of the amino acids that the 64 possible codons encode can be found at http://molbio.info.nih.gov/molbio/desk.html (choose "Table of Standard Genetic Code" for a codon table, and "Amino Acid Structure and Properties" for information regarding the amino acids). The three codons for which there is no matching tRNA (UAA, UGA, and UAG) serve as "stop-translation" signals at which the ribosome falls off.
Protein synthesis
After having discussed DNA and the various RNAs, the stage has been set for protein synthesis. The basic reaction of protein synthesis is the controlled formation of a peptide bond between two amino acids. This reaction is repeated many times, as each amino acid in turn is added to the growing polypeptide. Protein synthesis starts when the mRNA binds to a small ribosomal subunit near a AUG sequence in the mRNA. The AUG codon is called start codon, since it codes for the first amino acid (a methionine) to be made of the protein. The AUG codon base-pairs with the anticodon of tRNA carrying methionine. A large ribosomal subunit binds to the complex, and the reactions of protein synthesis itself can begin. The aminoacyl-tRNA to be called for next is determined by the next codon (the next three bases) on the mRNA. Each amino acid is coded for by one or more (up to six) codons. Of course, it would be more straightforward to have each amino acid coded for by only one codon, but nature appears to have chosen a more complex route. The reason for this in part is that there are 20 different amino acids, and 4x4x4=64 different combinations possible in a codon. When the ribosome reaches one of the three codons for which there is no matching tRNA, the ribosome falls off and the synthesized protein is released. The degeneracy of the genetic code for certain amino acids could have a function in regulation of translation; any idea how? The process of protein synthesis has been summarized on pages 34-38 of Molecular Biotechnology, and can also be found on the web at http://accessexcellence.org/AB/GG/protein_synthesis.html translation (in conjunction with transcription) and http://accessexcellence.org/AB/GG/dna_molecule.html.
Amino acids represent quite a broad spectrum of different chemical structures. The web address http://www.ch.cam.ac.uk/magnus/molecules/amino/provides the structure of all amino acids. With the generation of a protein with a specific amino acid sequence using essentially the genetic information present in the DNA, the link between genetic and functional information is complete.
RNA editing
Over the last several years, it has become obvious that the sequence present in DNA does not always dictate literally the sequence of the protein. In a number of instances "RNA editing" has been observed (particularly in the small genomes present in mitochondria and chloroplasts), in which transcripts are chemically modified (for example, some Cs are changed to Us) by enzymes before translation takes place. Thus, the DNA sequence in such cases does not precisely correlate with the sequence of the gene product (the protein). One thus needs to compare sequences from DNA and protein (or from DNA and processed RNA) if one suspects that RNA editing can occur. The function of RNA editing has not been elucidated yet.
Questions, Chapter 3
1.
Just to provide yourself with a perspective on how much genetic flexibility there is, calculate how many different sequences of 150 nucleotides long could exist that would code for a short, 50-amino-acid protein. And how many different ways are there to make a short protein of 50 amino acids? What would be the answer if you had a large, 6000 nucleotide long sequence that coded for a large protein of 2000 amino acids?
2.
Some prokaryotes grow at very high temperature (70-100 °C) and are called thermophiles. Organisms living in the deep sea where the pressure (and thus the boiling point of water) is very high grow at even higher temperatures and are called extremophiles. A group of these prokaryotes, named archaea, have now been found to contain DNA-binding proteins, whereas other thermophilic prokaryotes are found to have a very high GC content (and thus a low AT content) in their DNA. Can you explain why this would be?
Heterocyclic Amines
Heterocyclic amines are sometimes called nitrogen bases or simply bases. The heterocyclic amines are derived from two root structures: purines or pyrimidines. The purine root has both a six and a five member ring; the pyrimidine has a single six member ring.
There are two major purines, adenine (A) and guanine (G), and three major pyrimidines, cytosine (C), uracil (U), and thymine (T). The structures are shown in the graphic on the left. As you can see, these structures are called "bases" because the amine groups as part of the ring or as a side chain have a basic property in water.
A major difference between DNA and RNA is that DNA contains thymine, but not uracil, while RNA contains uracil but not thymine. The other three heterocyclic amines, adenine, guanine, and cytosine are found in both DNA and RNA. For convenience, you may remember, the list of heterocyclic amines in DNA by the words: The Amazing Gene Code (TAGC).
DNA and RNA Introduction
The nucleic acids are informational molecules because their primary structure contains a code or set of directions by which they can duplicate themselves and guide the synthesis of proteins. The synthesis of proteins - most of which are enzymes - ultimately governs the metabolic activities of the cell. In 1953, Watson, an American biologist, and Crick, an English biologist, proposed the double helix structure for DNA. This development set the stage for a new and continuing era of chemical and biological investigation. The two main events in the life of a cell - dividing to make exact copies of themselves, and manufacturing proteins - both rely on blueprints coded in our genes.
There are two types of nucleic acids which are polymers found in all living cells. Deoxyribonucleic Acid (DNA) is found mainly in the nucleus of the cell, while Ribonucleic Acid (RNA) is found mainly in the cytoplasm of the cell although it is usually synthesized in the nucleus. DNA contains the genetic codes to make RNA and the RNA in turn then contains the codes for the primary sequence of amino acids to make proteins.
Nucleic Acid Parts List:
The best way to understand the structures of DNA and RNA is to identify and examine individual parts of the structures first. The complete hydrolysis of nucleic acids yields three major classes of compounds: pentose sugars, phosphates, and heterocyclic amines (or bases).
Phosphate: A major requirement of all living things is a suitable source of phosphorus. One of the major uses for phosphorus is as the phosphate ion which is incorporated into DNA and RNA.
Pentose Sugars:
There are two types of pentose sugars found in nucleic acids. This difference is reflected in their names--deoxyribonucleic acid indicates the presence of deoxyribose; while ribonucleic acid indicates the presence of ribose.
In the graphic on the left, the structures of both ribose and deoxyribose are shown. Note the red -OH on one and the red -H on the other are the only differences. The alpha and beta designations are interchangeable and are not a significant difference between the two.
