All apes apart from man have 24 pairs of chromosomes. There is therefore a hypothesis that the common ancestor of all great apes had 24 pairs of chromosomes and that the fusion of two of the ancestor's chromosomes created chromosome 2 in humans. The evidence for this hypothesis is very strong.
The Evidence
Evidence for fusing of two ancestral chromosomes to create human chromosome 2 and where there has been no fusion in other Great Apes is:
1) The analogous chromosomes (2p and 2q) in the non-human great apes can be shown, when laid end to end, to create an identical banding structure to the human chromosome 2.
2) The remains of the sequence that the chromosome has on its ends (the telomere) is found in the middle of human chromosome 2 where the ancestral chromosomes fused.
3) the detail of this region (pre-telomeric sequence, telomeric sequence, reversed telomeric sequence, pre-telomeric sequence) is exactly what we would expect from a fusion.
4) this telomeric region is exactly where one would expect to find it if a fusion had occurred in the middle of human chromosome 2.
5) the centromere of human chromosome 2 lines up with the chimp chromosome 2p chromosomal centromere.
6) At the place where we would expect it on the human chromosome we find the remnants of the chimp 2q centromere .
Not only is this strong evidence for a fusion event, but it is also strong evidence for common ancestry; in fact, it is hard to explain by any other mechanism.
Centromere evidence
Let us re-iterate what we find on human chromosome 2. Its centromere is at the same place as the chimpanzee chromosome 2p as determined by sequence similarity. Even more telling is the fact that on the 2q arm of the human chromosome 2 is the unmistakable remains of the original chromosome centromere of the common ancestor of human and chimp 2q chromosome, at the same position as the chimp 2q centromere (this structure in humans no longer acts as a centromere for chromosome 2.
Refered
http://www.evolutionpages.com/chromosome_2.htm
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Showing posts with label Human Genome. Show all posts
Showing posts with label Human Genome. Show all posts
Tuesday, December 16, 2008
Monday, December 15, 2008
The Human Genome Project
The Human Genome Project (HGP) was an international scientific research project with a primary goal to determine the sequence of chemical base pairs which make up DNA and to identify the approximately 25,000 genes of the human genome from both a physical and functional standpoint.
The project began in 1990 initially headed by James D. Watson at the U.S. National Institutes of Health. A working draft of the genome was released in 2000 and a complete one in 2003, with further analysis still being published. A parallel project was conducted by the private company Celera Genomics. Most of the sequencing was performed in universities and research centers from the United States, Canada and Great Britain. The mapping of human genes is an important step in the development of medicines and other aspects of health care.
hile the objective of the Human Genome Project is to understand the genetic makeup of the human species, the project also has focused on several other nonhuman organisms such as E. coli, the fruit fly, and the laboratory mouse. It remains one of the largest single investigational projects in modern science.
The HGP originally aimed to map the nucleotides contained in a haploid reference human genome (more than three billion). Several groups have announced efforts to extend this to diploid human genomes including the International HapMap Project, Applied Biosystems, Perlegen, Illumina, JCVI, Personal Genome Project, and Roche-454.
The "genome" of any given individual (except for identical twins and cloned animals) is unique; mapping "the human genome" involves sequencing multiple variations of each gene. The project did not study the entire DNA found in human cells; some heterochromatic areas (about 8% of the total) remain un-sequenced.
Background
Initiation of the Project was the culmination of several years of work supported by the United States Department of Energy, in particular workshops in 1984 and 1986 and a subsequent initiative the US Department of Energy.This 1987 report stated boldly, "The ultimate goal of this initiative is to understand the human genome" and "knowledge of the human genome is as necessary to the continuing progress of medicine and other health sciences as knowledge of human anatomy has been for the present state of medicine." Candidate technologies were already being considered for the proposed undertaking at least as early as 1985.
James D. Watson was head of the National Center for Human Genome Research at the National Institutes of Health (NIH) in the United States starting from 1988. Largely due to his disagreement with his boss, Bernadine Healy, over the issue of patenting genes, he was forced to resign in 1992. He was replaced by Francis Collins in April 1993, and the name of the Center was changed to the National Human Genome Research Institute (NHGRI) in 1997.
The $3-billion project was formally founded in 1990 by the United States Department of Energy and the U.S. National Institutes of Health, and was expected to take 15 years. In addition to the United States, the international consortium comprised geneticists in China, France, Germany, Japan, and the United Kingdom.
Due to widespread international cooperation and advances in the field of genomics (especially in sequence analysis), as well as major advances in computing technology, a 'rough draft' of the genome was finished in 2000 (announced jointly by then US president Bill Clinton and British Prime Minister Tony Blair on June 26, 2000).Ongoing sequencing led to the announcement of the essentially complete genome in April 2003, 2 years earlier than planned.In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the last chromosome was published in the journal Nature.
State of completion
There are multiple definitions of the "complete sequence of the human genome". According to some of these definitions, the genome has already been completely sequenced, and according to other definitions, the genome has yet to be completely sequenced. There have been multiple popular press articles reporting that the genome was "complete." The genome has been completely sequenced using the definition employed by the International Human Genome Project. A graphical history of the human genome project shows that most of the human genome was complete by the end of 2003. However, there are a number of regions of the human genome that can be considered unfinished:
First, the central regions of each chromosome, known as centromeres, are highly repetitive DNA sequences that are difficult to sequence using current technology. The centromeres are millions (possibly tens of millions) of base pairs long, and for the most part these are entirely un-sequenced.
Second, the ends of the chromosomes, called telomeres, are also highly repetitive, and for most of the 46 chromosome ends these too are incomplete. It is not known precisely how much sequence remains before the telomeres of each chromosome are reached, but as with the centromeres, current technological restraints are prohibitive.
Third, there are several loci in each individual's genome that contain members of multigene families that are difficult to disentangle with shotgun sequencing methods - these multigene families often encode proteins important for immune functions.
Other than these regions, there remain a few dozen gaps scattered around the genome, some of them rather large, but there is hope that all these will be closed in the next couple of years.
In summary: the best estimates of total genome size indicate that about 92% of the genome has been completed and it is likely that the centromeres and telomeres will remain un-sequenced until new technology is developed that facilitates their sequencing. Most of the remaining DNA is highly repetitive and unlikely to contain genes, but it cannot be truly known until it is entirely sequenced. Understanding the functions of all the genes and their regulation is far from complete. The roles of junk DNA, the evolution of the genome, the differences between individuals, and many other questions are still the subject of intense interest by laboratories all over the world.
Goals
The sequence of the human DNA is stored in databases available to anyone on the Internet. The U.S. National Center for Biotechnology Information (and sister organizations in Europe and Japan) house the gene sequence in a database known as Genbank, along with sequences of known and hypothetical genes and proteins. Other organizations such as the University of California, Santa Cruz, and Ensembl present additional data and annotation and powerful tools for visualizing and searching it. Computer programs have been developed to analyze the data, because the data themselves are difficult to interpret without such programs.
The process of identifying the boundaries between genes and other features in raw DNA sequence is called genome annotation and is the domain of bioinformatics. While expert biologists make the best annotators, their work proceeds slowly, and computer programs are increasingly used to meet the high-throughput demands of genome sequencing projects. The best current technologies for annotation make use of statistical models that take advantage of parallels between DNA sequences and human language, using concepts from computer science such as formal grammars.
Another, often overlooked, goal of the HGP is the study of its ethical, legal, and social implications. It is important to research these issues and find the most appropriate solutions before they become large dilemmas whose effect will manifest in the form of major political concerns.
All humans have unique gene sequences. Therefore the data published by the HGP does not represent the exact sequence of each and every individual's genome. It is the combined genome of a small number of anonymous donors. The HGP genome is a scaffold for future work in identifying differences among individuals. Most of the current effort in identifying differences among individuals involves single nucleotide polymorphisms and the HapMap.
Almost all the goals that the Human Genome Project has set for itself have been completed earlier than predicted. The Human Genome Project actually exceeded the projected finishing time by two years. The Human Genome Project set a reasonable, attainable goal of 95% of DNA to be sequenced. Not only did the researchers surpass that goal, they shattered their prediction, and were able to sequence 99.99% of a human's DNA. Not only did The Human Genome Project exceed all goals and standards, it still continues making progress on those goals already achieved.
How it was accomplished
Funding came from the US government through the National Institutes of Health in the United States, and the UK charity, the Wellcome Trust, who funded the Sanger Institute (then the Sanger Centre) in Great Britain, as well as numerous other groups from around the world. The genome was broken into smaller pieces; approximately 150,000 base pairs in length. These pieces were then spliced into a type of vector known as "bacterial artificial chromosomes", or BACs, which are derived from bacterial chromosomes which have been genetically engineered. The vectors containing the genes can be inserted into bacteria where they are copied by the bacterial DNA replication machinery. Each of these pieces was then sequenced separately as a small "shotgun" project and then assembled. The larger, 150,000 base pairs go together to create chromosomes. This is known as the "hierarchical shotgun" approach, because the genome is first broken into relatively large chunks, which are then mapped to chromosomes before being selected for sequencing.
The project began in 1990 initially headed by James D. Watson at the U.S. National Institutes of Health. A working draft of the genome was released in 2000 and a complete one in 2003, with further analysis still being published. A parallel project was conducted by the private company Celera Genomics. Most of the sequencing was performed in universities and research centers from the United States, Canada and Great Britain. The mapping of human genes is an important step in the development of medicines and other aspects of health care.
hile the objective of the Human Genome Project is to understand the genetic makeup of the human species, the project also has focused on several other nonhuman organisms such as E. coli, the fruit fly, and the laboratory mouse. It remains one of the largest single investigational projects in modern science.
The HGP originally aimed to map the nucleotides contained in a haploid reference human genome (more than three billion). Several groups have announced efforts to extend this to diploid human genomes including the International HapMap Project, Applied Biosystems, Perlegen, Illumina, JCVI, Personal Genome Project, and Roche-454.
The "genome" of any given individual (except for identical twins and cloned animals) is unique; mapping "the human genome" involves sequencing multiple variations of each gene. The project did not study the entire DNA found in human cells; some heterochromatic areas (about 8% of the total) remain un-sequenced.
Background
Initiation of the Project was the culmination of several years of work supported by the United States Department of Energy, in particular workshops in 1984 and 1986 and a subsequent initiative the US Department of Energy.This 1987 report stated boldly, "The ultimate goal of this initiative is to understand the human genome" and "knowledge of the human genome is as necessary to the continuing progress of medicine and other health sciences as knowledge of human anatomy has been for the present state of medicine." Candidate technologies were already being considered for the proposed undertaking at least as early as 1985.
James D. Watson was head of the National Center for Human Genome Research at the National Institutes of Health (NIH) in the United States starting from 1988. Largely due to his disagreement with his boss, Bernadine Healy, over the issue of patenting genes, he was forced to resign in 1992. He was replaced by Francis Collins in April 1993, and the name of the Center was changed to the National Human Genome Research Institute (NHGRI) in 1997.
The $3-billion project was formally founded in 1990 by the United States Department of Energy and the U.S. National Institutes of Health, and was expected to take 15 years. In addition to the United States, the international consortium comprised geneticists in China, France, Germany, Japan, and the United Kingdom.
Due to widespread international cooperation and advances in the field of genomics (especially in sequence analysis), as well as major advances in computing technology, a 'rough draft' of the genome was finished in 2000 (announced jointly by then US president Bill Clinton and British Prime Minister Tony Blair on June 26, 2000).Ongoing sequencing led to the announcement of the essentially complete genome in April 2003, 2 years earlier than planned.In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the last chromosome was published in the journal Nature.
State of completion
There are multiple definitions of the "complete sequence of the human genome". According to some of these definitions, the genome has already been completely sequenced, and according to other definitions, the genome has yet to be completely sequenced. There have been multiple popular press articles reporting that the genome was "complete." The genome has been completely sequenced using the definition employed by the International Human Genome Project. A graphical history of the human genome project shows that most of the human genome was complete by the end of 2003. However, there are a number of regions of the human genome that can be considered unfinished:
First, the central regions of each chromosome, known as centromeres, are highly repetitive DNA sequences that are difficult to sequence using current technology. The centromeres are millions (possibly tens of millions) of base pairs long, and for the most part these are entirely un-sequenced.
Second, the ends of the chromosomes, called telomeres, are also highly repetitive, and for most of the 46 chromosome ends these too are incomplete. It is not known precisely how much sequence remains before the telomeres of each chromosome are reached, but as with the centromeres, current technological restraints are prohibitive.
Third, there are several loci in each individual's genome that contain members of multigene families that are difficult to disentangle with shotgun sequencing methods - these multigene families often encode proteins important for immune functions.
Other than these regions, there remain a few dozen gaps scattered around the genome, some of them rather large, but there is hope that all these will be closed in the next couple of years.
In summary: the best estimates of total genome size indicate that about 92% of the genome has been completed and it is likely that the centromeres and telomeres will remain un-sequenced until new technology is developed that facilitates their sequencing. Most of the remaining DNA is highly repetitive and unlikely to contain genes, but it cannot be truly known until it is entirely sequenced. Understanding the functions of all the genes and their regulation is far from complete. The roles of junk DNA, the evolution of the genome, the differences between individuals, and many other questions are still the subject of intense interest by laboratories all over the world.
Goals
The sequence of the human DNA is stored in databases available to anyone on the Internet. The U.S. National Center for Biotechnology Information (and sister organizations in Europe and Japan) house the gene sequence in a database known as Genbank, along with sequences of known and hypothetical genes and proteins. Other organizations such as the University of California, Santa Cruz, and Ensembl present additional data and annotation and powerful tools for visualizing and searching it. Computer programs have been developed to analyze the data, because the data themselves are difficult to interpret without such programs.
The process of identifying the boundaries between genes and other features in raw DNA sequence is called genome annotation and is the domain of bioinformatics. While expert biologists make the best annotators, their work proceeds slowly, and computer programs are increasingly used to meet the high-throughput demands of genome sequencing projects. The best current technologies for annotation make use of statistical models that take advantage of parallels between DNA sequences and human language, using concepts from computer science such as formal grammars.
Another, often overlooked, goal of the HGP is the study of its ethical, legal, and social implications. It is important to research these issues and find the most appropriate solutions before they become large dilemmas whose effect will manifest in the form of major political concerns.
All humans have unique gene sequences. Therefore the data published by the HGP does not represent the exact sequence of each and every individual's genome. It is the combined genome of a small number of anonymous donors. The HGP genome is a scaffold for future work in identifying differences among individuals. Most of the current effort in identifying differences among individuals involves single nucleotide polymorphisms and the HapMap.
Almost all the goals that the Human Genome Project has set for itself have been completed earlier than predicted. The Human Genome Project actually exceeded the projected finishing time by two years. The Human Genome Project set a reasonable, attainable goal of 95% of DNA to be sequenced. Not only did the researchers surpass that goal, they shattered their prediction, and were able to sequence 99.99% of a human's DNA. Not only did The Human Genome Project exceed all goals and standards, it still continues making progress on those goals already achieved.
How it was accomplished
Funding came from the US government through the National Institutes of Health in the United States, and the UK charity, the Wellcome Trust, who funded the Sanger Institute (then the Sanger Centre) in Great Britain, as well as numerous other groups from around the world. The genome was broken into smaller pieces; approximately 150,000 base pairs in length. These pieces were then spliced into a type of vector known as "bacterial artificial chromosomes", or BACs, which are derived from bacterial chromosomes which have been genetically engineered. The vectors containing the genes can be inserted into bacteria where they are copied by the bacterial DNA replication machinery. Each of these pieces was then sequenced separately as a small "shotgun" project and then assembled. The larger, 150,000 base pairs go together to create chromosomes. This is known as the "hierarchical shotgun" approach, because the genome is first broken into relatively large chunks, which are then mapped to chromosomes before being selected for sequencing.
Alu sequence
Alu sequence is a short stretch of DNA originally characterized by the action of the Alu restriction endonuclease. Alu sequences of different kinds occur in large numbers in primate genomes. In fact, Alu sequences are the most abundant mobile elements in the human genome. They are derived from the small cytoplasmic 7SL RNA, a component of the signal recognition particle. The event, when a copy of the 7SL RNA became a precursor of the Alu sequence, took place in the genome of an ancestor of Supraprimates.
Transcript
The bulk of human genome contains many sequence that do not code for any protein. These regions of genome are sometimes referred to as "junk" Dna,and make up more than 98% pf human genome.Included in the non-coding dna are many repetitive dna sequences. Two important families of repetitive elements are LINEs(Long Interspersed Elements) and the SINEs(Short Interspersed Elements).L1 is the most prevalent LINEs, and makes up about 17% of human genome.
Alu is the most prevalent SINEs,and equals about 11% of the genome,Alu and other SINEs are "defective" transposons;they depend on the enzymes of other transposons like L1,for mobility.It is estimated that there are about 75000 L1 and 1200000 Alu elements distributed throughout the human genome. Lets take a closer look at a single copy of each
L1 ,at approximately 20 times the length of Alu,encodes all the molecular machinery needed to replicate and move within the genome.An l1 element is approximately 6000 nucleotides in length, with two untranslated regions(UTRs)and two open reading frames(ORFs).
The ORF protein products assemble into complex that enables L1 and elements such as Alu to move throughout the genome.The structure of L1 is a stark contrast with that of the tiny 300 nucleotide Alu,Alu elements have no open reading frames and so encode no proteins.
Alu elements are characterized by a sequence with two G/C rich regions: the let(L-Alu) and the right(R-Alu) monomers. An A-rich linker connects these monomers. Alu elements end with a poly-A tail.In the genome, Alu elements are immediately flanked by A=T rich sequences.
The L-Alu regions contains two specific features Box A and Box B,which are binding sites of transcription factors and RNA polymerase III.Alu elements are transcribed into RNA by these proteins until they reach a stretch of T's is the genomic DNA.
The Alu Rna can act as template for the formation of a new Alu element that can itself in a new genome location. A likely model for this process requires the enzyme, a reverse transcriptase(rt),encoded by L1.
In addition to reverse transcription,L1 rt has teh unique ability to nick DNA in a site-preferential manner. Most ofen the nick is made at the consensus sequence TTAAA.This can create a single-stranded sequences of Ts that hydrogen bonds with the poly-A tail of the Alu RNA to form a short RNA/DNA heteroduplex.
The heteroduplex than can serve as a primer for L1 rt to synthesize a complementary (c) DNA strand.
A second nick is mode on the opposite strand, a variable distance from the initial cleavage site. Then, either the L1 rt or a cellular Dna polymerase synthesizes the second DNA strand.
This results in an Alu element inserted into a novel position of the genome. The insertion also creates a direct repeat sequence on either side of the element.
Transcript
The bulk of human genome contains many sequence that do not code for any protein. These regions of genome are sometimes referred to as "junk" Dna,and make up more than 98% pf human genome.Included in the non-coding dna are many repetitive dna sequences. Two important families of repetitive elements are LINEs(Long Interspersed Elements) and the SINEs(Short Interspersed Elements).L1 is the most prevalent LINEs, and makes up about 17% of human genome.
Alu is the most prevalent SINEs,and equals about 11% of the genome,Alu and other SINEs are "defective" transposons;they depend on the enzymes of other transposons like L1,for mobility.It is estimated that there are about 75000 L1 and 1200000 Alu elements distributed throughout the human genome. Lets take a closer look at a single copy of each
L1 ,at approximately 20 times the length of Alu,encodes all the molecular machinery needed to replicate and move within the genome.An l1 element is approximately 6000 nucleotides in length, with two untranslated regions(UTRs)and two open reading frames(ORFs).
The ORF protein products assemble into complex that enables L1 and elements such as Alu to move throughout the genome.The structure of L1 is a stark contrast with that of the tiny 300 nucleotide Alu,Alu elements have no open reading frames and so encode no proteins.
Alu elements are characterized by a sequence with two G/C rich regions: the let(L-Alu) and the right(R-Alu) monomers. An A-rich linker connects these monomers. Alu elements end with a poly-A tail.In the genome, Alu elements are immediately flanked by A=T rich sequences.
The L-Alu regions contains two specific features Box A and Box B,which are binding sites of transcription factors and RNA polymerase III.Alu elements are transcribed into RNA by these proteins until they reach a stretch of T's is the genomic DNA.
The Alu Rna can act as template for the formation of a new Alu element that can itself in a new genome location. A likely model for this process requires the enzyme, a reverse transcriptase(rt),encoded by L1.
In addition to reverse transcription,L1 rt has teh unique ability to nick DNA in a site-preferential manner. Most ofen the nick is made at the consensus sequence TTAAA.This can create a single-stranded sequences of Ts that hydrogen bonds with the poly-A tail of the Alu RNA to form a short RNA/DNA heteroduplex.
The heteroduplex than can serve as a primer for L1 rt to synthesize a complementary (c) DNA strand.
A second nick is mode on the opposite strand, a variable distance from the initial cleavage site. Then, either the L1 rt or a cellular Dna polymerase synthesizes the second DNA strand.
This results in an Alu element inserted into a novel position of the genome. The insertion also creates a direct repeat sequence on either side of the element.
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