Human chromosomes range in size from about 50,, to ,, base pairs. Because the bases exist as pairs, and the identity of one of the bases in the pair determines the other member of the pair, scientists do not have to report both bases of the pair. The primary method used by the HGP to produce the finished version of the human genetic code was map-based, or BAC-based, sequencing.
BAC is the acronym for "bacterial artificial chromosome. The fragments are cloned in bacteria, which store and replicate the human DNA so that it can be prepared in quantities large enough for sequencing. If carefully chosen to minimize overlap, it takes about 20, different BAC clones to contain the 3 billion pairs of bases of the human genome.
Using this approach ensures that scientists know both the precise location of the DNA letters that are sequenced from each clone and their spatial relation to sequenced human DNA in other BAC clones. For sequencing, each BAC clone is cut into still smaller fragments that are about 2, bases in length. These pieces are called "subclones. The products of the sequencing reaction are then loaded into the sequencing machine sequencer.
The sequencer generates about to base pairs of A, T, C and G from each sequencing reaction, so that each base is sequenced about 10 times. A computer then assembles these short sequences into contiguous stretches of sequence representing the human DNA in the BAC clone. This was intentionally not known to protect the volunteers who provided DNA samples for sequencing.
The sequence is derived from the DNA of several volunteers. To ensure that the identities of the volunteers cannot be revealed, a careful process was developed to recruit the volunteers and to collect and maintain the blood samples that were the source of the DNA.
The volunteers responded to local public advertisements near the laboratories where the DNA "libraries" were prepared. Candidates were recruited from a diverse population. The volunteers provided blood samples after being extensively counseled and then giving their informed consent. About 5 to 10 times as many volunteers donated blood as were eventually used, so that not even the volunteers would know whether their sample was used.
All labels were removed before the actual samples were chosen. The main goals of the Human Genome Project were first articulated in by a special committee of the U.
Mistakes that are duplicated in subsequent copies are called mutations. Inherited mutations are those that may be passed on to offspring.
Mutations can be inherited only when they affect the reproductive cells sperm or egg. Mutations that do not affect reproductive cells affect the descendants of the mutated cell for example, becoming a cancer but are not passed on to offspring.
Mutations may be unique to an individual or family, and most harmful mutations are rare. Mutations may involve small or large segments of DNA. Depending on its size and location, the mutation may have no apparent effect or it may alter the amino acid sequence in a protein or decrease the amount of protein produced.
If the protein has a different amino acid sequence, it may function differently or not at all. An absent or nonfunctioning protein is often harmful or fatal. For example, in phenylketonuria Phenylketonuria PKU Phenylketonuria is a disorder of amino acid metabolism that occurs in infants born without the ability to normally break down an amino acid called phenylalanine. Phenylalanine, which is toxic This deficiency allows the amino acid phenylalanine absorbed from the diet to accumulate in the body, ultimately causing severe intellectual disability.
In rare cases, a mutation introduces a change that is advantageous. For example, in the case of the sickle cell gene, when a person inherits two copies of the abnormal gene, the person will develop sickle cell disease Sickle Cell Disease Sickle cell disease is an inherited genetic abnormality of hemoglobin the oxygen-carrying protein found in red blood cells characterized by sickle crescent -shaped red blood cells and chronic However, when a person inherits only one copy of the sickle cell gene called a carrier , the person develops some protection against malaria Malaria Malaria is infection of red blood cells with one of five species of Plasmodium, a protozoan.
Malaria causes fever, chills, sweating, a general feeling of illness malaise , and sometimes diarrhea Although the protection against malaria can help a carrier survive, sickle cell disease in a person who has two copies of the gene causes symptoms and complications that may shorten life span.
Natural selection refers to the concept that mutations that impair survival in a given environment are less likely to be passed on to offspring and thus become less common in the population , whereas mutations that improve survival progressively become more common. Thus, beneficial mutations, although initially rare, eventually become common. The slow changes that occur over time caused by mutations and natural selection in an interbreeding population collectively are called evolution.
Not all gene abnormalities are harmful. For example, the gene that causes sickle cell disease also provides protection against malaria. A chromosome is made of a very long strand of DNA and contains many genes Genes Genes are segments of deoxyribonucleic acid DNA that contain the code for a specific protein that functions in one or more types of cells in the body.
The genes on each chromosome are arranged in a particular sequence, and each gene has a particular location on the chromosome called its locus. In addition to DNA, chromosomes contain other chemical components that influence gene function. Except for certain cells for example, sperm and egg cells or red blood cells , the nucleus of every normal human cell contains 23 pairs of chromosomes, for a total of 46 chromosomes.
Normally, each pair consists of one chromosome from the mother and one from the father. There are 22 pairs of nonsex autosomal chromosomes and one pair of sex chromosomes. Paired nonsex chromosomes are, for practical purposes, identical in size, shape, and position and number of genes. Because each member of a pair of nonsex chromosomes contains one of each corresponding gene, there is in a sense a backup for the genes on those chromosomes.
The pair of sex chromosomes determines whether a fetus becomes male or female. Males have one X and one Y chromosome. Females have two X chromosomes, one from the mother and one from the father. In certain ways, sex chromosomes function differently than nonsex chromosomes.
The smaller Y chromosome carries the genes that determine male sex as well as a few other genes. The X chromosome contains many more genes than the Y chromosome, many of which have functions besides determining sex and have no counterpart on the Y chromosome.
In males, because there is no second X chromosome, these extra genes on the X chromosome are not paired and virtually all of them are expressed. Genes on the X chromosome are referred to as sex-linked, or X-linked, genes.
Normally, in the nonsex chromosomes, the genes on both of the pairs of chromosomes are capable of being fully expressed. However, in females, most of the genes on one of the two X chromosomes are turned off through a process called X inactivation except in the eggs in the ovaries. X inactivation occurs early in the life of the fetus. In some cells, the X from the father becomes inactive, and in other cells, the X from the mother becomes inactive. Because of X inactivation, the absence of one X chromosome usually results in relatively minor abnormalities such as Turner syndrome Turner Syndrome Turner syndrome is a sex chromosome abnormality in which girls are born with one of their two X chromosomes partially or completely missing.
Turner syndrome is caused by the deletion of part Mitochondria are the cell's power plants, and many of their genes are involved in production of cellular energy. They have their own set of genes because they are thought to have evolved from bacteria that were engulfed by eukaryotic cells cells containing a nucleus some 1. That's how many feet long the DNA from one of your cells would be if you uncoiled each strand and placed them end to end.
Do this for all your DNA, and the resulting strand would be 67 billion miles long—the same as about , round trips to the Moon. That's the length in inches across a cell's nucleus, which holds your DNA. If you sliced human hair into tenths lengthwise, each slice would be about that big around. To keep the space tidy, DNA spools around a group of proteins called histones. The resulting taut package of wound-up DNA is called chromatin, which winds up even tighter to form your chromosomes.
The DNA of any two people on Earth is But 0. Our environment also contributes to our individuality. That's the fraction of human genes estimated to be regulated by microRNAs. These genetic "micromanagers" consist of only about 22 RNA units called nucleotides, but they can stop a gene from producing the protein it encodes. The human genome began with the assumption that our genome contains , protein-coding genes, and estimates published in the s revised this number slightly downward, usually reporting values between 50, and , The two initial human genome papers reported 31, [ 2 ] and 26, protein-coding genes [ 3 ], and when the more complete draft of the genome appeared in [ 4 ], the authors estimated that a complete catalog would contain 24, protein-coding genes.
The Ensembl human gene catalog described in that paper version 34d had 22, protein-coding genes and 34, transcripts. The invention of RNA-seq in [ 5 , 6 ], which was designed to improve our ability to quantify gene expression, also greatly enhanced our ability to detect transcribed sequences, both coding and noncoding. The implication of these findings is that even if we know where all the genes are, we still have considerable work to discover all the isoforms of those genes, and yet more work to determine whether these isoforms have any function or if they just represent splicing errors, as some have argued [ 9 ].
The challenge of identifying all human genes still confronts us. Even after all this time—despite much progress—the two catalogs today have hundreds of disagreements between their lists of protein-coding genes, thousands of inconsistencies between their lncRNAs, and multiple categories of genes e.
The two catalogs are also still evolving; for example, in the past year alone, hundreds of protein-coding genes have been added to or deleted from the Gencode list. These disagreements highlight the ongoing challenge of creating a comprehensive human gene catalog. The problem of finding all human genes is too important to leave in the hands of just two groups, especially given the lack of agreement in current databases.
In , we created a new human gene database, CHESS, that used a massive RNA-seq collection to assemble anew all of the transcripts from a broad survey of human tissues, which is available as a preprint [ 10 ]. By design, it includes all of the protein-coding genes from both Gencode and RefSeq, so that users of CHESS do not have to decide which database they prefer.
Its larger number of genes may include more false positives, but we believe the larger set will nonetheless prove very useful, especially to the many studies of human disease that have not yet found a genetic cause. Many genes especially lncRNAs appear to be highly tissue-specific, and until we survey all human cell types more thoroughly—which may take many more years—we cannot be sure that we have discovered all human genes and transcripts.
For most other animal and plant species, we know even less about their gene catalogs, although our knowledge is rapidly improving. Our inability to find a simple answer to the fundamental question of the HGP does not mean we have failed, however. On the contrary, our knowledge of human genes is vastly richer than it was at the outset of the HGP, and technological advances of the past decade provide me with optimism that we will eventually pin down this number.
Understanding our genetic inheritance: the U. Human Genome Project, the first five years
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