Working with Molecular Genetics

The New Genetics

In women, the likelihood that chromosomes won't be apportioned properly increases with age. One of every 18 babies born to women over 45 has three copies of chromosome 13, 18 or 21 instead of the normal two, and this improper balancing can cause trouble. For example, three copies of chromosome 21 lead to Down syndrome.

To make her work easier, Amon—like many other basic scientists—studies yeast cells, which separate their chromosomes almost exactly the same way human cells do, except that yeast do it much faster. The yeast cells she uses are the same kind bakeries use to make bread and breweries use to make beer! Amon has made major progress in understanding the details of meiosis. Her research shows how, in healthy cells, gluelike protein complexes called cohesins release pairs of chromosomes at exactly the right time.

This allows the chromosomes to separate properly. These findings have important implications for understanding and treating infertility, birth defects and cancer. So, we've described DNA—its basic properties and how our bodies make more of it. But how does DNA serve as the language of life? How do you get a protein from a gene? There are two major steps in making a protein. This copy is called messenger RNA, or mRNA, because it delivers the gene's message to the protein-producing machinery.

At this point you may be wondering why all of the cells in the human body aren't exactly alike, since they all contain the same DNA. What makes a liver cell different from a brain cell? How do the cells in the heart make the organ contract, but those in skin allow us to sweat? Cells can look and act differently, and do entirely different jobs, because each cell "turns on," or expresses, only the genes appropriate for what it needs to do. That's because RNA polymerase does not work alone, but rather functions with the aid of many helper proteins.

While the core part of RNA polymerase is the same in all cells, the helpers vary in different cell types throughout the body. You'd think that for a process so essential to life, researchers would know a lot about how transcription works.

While it's true that the basics are clear—biologists have been studying gene transcribing by RNA polymerases since these proteins were first discovered in — some of the details are actually still murky. The biggest obstacle to learning more has been a lack of tools. Until recently, researchers were unable to get a picture at the atomic level of the giant RNA polymerase protein assemblies inside cells to understand how the many pieces of this amazing, living machine do what they do, and do it so well.

But our understanding is improving fast, thanks to spectacular technological advances. We have new X-ray pictures that are far more sophisticated than those that revealed the structure of DNA. This work earned him the Nobel Prize in chemistry. In addition, very powerful microscopes and other tools that allow us to watch one molecule at a time provide a new look at RNA polymerase while it's at work reading DNA and producing RNA. Block and his team performed this work by designing a specialized microscope sensitive enough to watch the real-time motion of a single polymerase traveling down a gene on one chromosome.

The researchers discovered that molecules of RNA polymerase behave like battery-powered spiders as they crawl along the DNA ladder, adding nucleotides one at a time to the growing RNA strand. The enzyme works much like a motor, Block believes, powered by energy released during the chemical synthesis of RNA.

Several types of RNA play key roles in making a protein. Ribosomal RNA forms about 60 percent of the ribosomes. Lastly, transfer RNA carries amino acids to the ribosomes. As you can see, all three types of cellular RNAs come together to produce new proteins. But the journey from gene to protein isn't quite as simple as we've just made it out to be. After transcription, several things need to happen to mRNA before a protein can be made. For example, the genetic material of humans and other eukaryotes organisms that have a nucleus includes a lot of DNA that doesn't encode proteins.

Some of this DNA is stuck right in the middle of genes. To distinguish the two types of DNA, scientists call the coding sequences of genes exons and the pieces in between introns for intervening sequences. To get an mRNA molecule that yields a working protein, the cell needs to trim out the intron sections and then stitch only the exon pieces together see drawing. This process is called RNA splicing.

Splicing has to be extremely accurate. An error in the splicing process, even one that results in the deletion of just one nucleotide in an exon or the addition of just one nucleotide in an intron, will throw the whole sequence out of alignment. The result is usually an abnormal protein—or no protein at all. One form of Alzheimer's disease, for example, is caused by this kind of splicing error.

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Molecular biologist Christine Guthrie of the University of California, San Francisco, wants to understand more fully the mechanism for removing intron RNA and find out how it stays so accurate. She uses yeast cells for these experiments. Just like human DNA, yeast DNA has introns, but they are fewer and simpler in structure and are therefore easier to study. Guthrie can identify which genes are required for splicing by finding abnormal yeast cells that mangle splicing.

So why do introns exist, if they're just going to be chopped out? Without introns, cells wouldn't need to go through the splicing process and keep monitoring it to be sure it's working right. Think about all the exons in a gene. If a cell stitches together exons 1, 2 and 4, leaving out exon 3, the mRNA will specify the production of a particular protein.

But instead, if the cell stitches together exons 1, 2 and 3, this time leaving out exon 4, then the mRNA will be translated into a different protein see drawing. By cutting and pasting the exons in different patterns, which scientists call alternative splicing, a cell can create different proteins from a single gene. Alternative splicing is one of the reasons why human cells, which have about 20, genes, can make hundreds of thousands of different proteins. Until recently, researchers looked at genes, and the proteins they encode, one at a time.

Now, they can look at how large numbers of genes and proteins act, as well as how they interact. This gives them a much better picture of what goes on in a living organism. Already, scientists can identify all of the genes that are transcribed in a cell—or in an organ, like the heart. And although researchers can't tell you, right now, what's going on in every cell of your body while you read a book or walk down the street, they can do this sort of "whole-body" scan for simpler, single-celled organisms like yeast. Using a technique called genome-wide location analysis, Richard Young of the Massachusetts Institute of Technology unraveled a "regulatory code" of living yeast cells, which have more than 6, genes in their genome.

Since he did the experiment with the yeast exposed to a variety of different conditions,Young was able to figure out how transcription patterns differ when the yeast cell is under stress say, in a dry environment or thriving in a sugary-rich nutrient solution. Done one gene at a time, using methods considered state-of-the-art just a few years ago, this kind of analysis would have taken hundreds of years.

Careers in Clinical Molecular Genetics

After demonstrating that his technique worked in yeast, Young then took his research a step forward. He used a variation of the yeast method to scan the entire human genome in small samples of cells taken from the pancreases and livers of people with type 2 diabetes. He used the results to identify genes that aren't transcribed correctly in people with the disease. This information provides researchers with an important tool for understanding how diabetes and other diseases are influenced by defective genes. By building models to predict how genes respond in diverse situations, researchers may be able to learn how to stop or jump-start genes on demand, change the course of a disease or prevent it from ever happening.

While most genetic research uses lab organisms, test tubes and petri dishes, the results have real consequences for people. Your first encounter with genetic analysis probably happened shortly after you were born, when a doctor or nurse took a drop of blood from the heel of your tiny foot. Lab tests performed with that single drop of blood can diagnose certain rare genetic disorders as well as metabolic problems like phenylketonuria PKU. Screening newborns in this way began in the s in Massachusetts with testing for PKU, a disease affecting 1 in 14, people.

PKU is caused by an enzyme that doesn't work properly due to a genetic mutation. Those born with this disorder cannot metabolize the amino acid phenylalanine, which is present in many foods. Left untreated, PKU can lead to mental retardation and neurological damage, but a special diet can prevent these outcomes. Testing for this condition has made a huge difference in many lives. Newborn screening is governed by individual states. This means that the state in which a baby is born determines the genetic conditions for which he or she will be screened.

Currently, states test for between 28 and 54 conditions. All states test for PKU. Although expanded screening for genetic diseases in newborns is advocated by some, others question the value of screening for conditions that are currently untreatable. Another issue is that some children with mild versions of certain genetic diseases may be treated needlessly. Department of Health and Human Services, recommended a standard, national set of newborn tests for 29 conditions, ranging from relatively common hearing problems to very rare metabolic diseases.

After a gene has been read by RNA polymerase and the RNA is spliced, what happens next in the journey from gene to protein? The next step is reading the RNA information and fitting the building blocks of a protein together. This is called translation , and its principal actors are the ribosome and amino acids. Ribosomes are among the biggest and most intricate structures in the cell.

The ribosomes of bacteria contain not only huge amounts of RNA, but also more than 50 different proteins. Human ribosomes have even more RNA and between 70 and 80 different proteins! Harry Noller of the University of California, Santa Cruz, has found that a ribosome performs several key jobs when it translates the genetic code of mRNA. The ribosome also links each additional amino acid into a growing protein chain see drawing. For many years, researchers believed that even though RNAs formed a part of the ribosome, the protein portion of the ribosome did all of the work.

Noller thought, instead, that maybe RNA, not proteins, performed the ribosome's job. His idea was not popular at first, because at that time it was thought that RNA could not perform such complex functions. Some time later, however, the consensus changed. Noller and other researchers have continued the painstaking work of understanding ribosomes.

In , he showed how different parts of a bacterial ribosome interact with one another and how the ribosome interacts with molecules involved in protein synthesis. These studies provided near proof that the fundamental mechanism of translation is performed by RNA, not by the proteins of the ribosome. But which ribosomal RNAs are doing the work? Most scientists assumed that RNA nucleotides buried deep within the ribosome complex—the ones that have the same sequence in every species from bacteria to people—were the important ones for piecing the growing protein together.

However, recent research by Rachel Green, who worked with Noller before moving to Johns Hopkins University in Baltimore, Maryland, showed that this is not the case.

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Green discovered that those RNA nucleotides are not needed for assembling a protein. Instead, she found, the nucleotides do something else entirely: They help the growing protein slip off the ribosome once it's finished. Noller, Green and hundreds of other scientists work with the ribosomes of bacteria.

Why should you care about how bacteria create proteins from their genes? One reason is that this knowledge is important for learning how to disrupt the actions of disease-causing microorganisms. For example, antibiotics like erythromycin and neomycin work by attacking the ribosomes of bacteria, which are different enough from human ribosomes that our cells are not affected by these drugs. As researchers gain new information about bacterial translation, the knowledge may lead to more antibiotics for people. New antibiotics are urgently needed because many bacteria have developed resistance to the current arsenal.

This resistance is sometimes the result of changes in the bacteria's ribosomal RNA. It can be difficult to find those small, but critical, changes that may lead to resistance, so it is important to find completely new ways to block bacterial translation. Green is working on that problem too.

Her strategy is to make random mutations to the genes in a bacterium that affect its ribosomes. But what if the mutation disables the ribosome so much that it can't make proteins? Then the bacterium won't grow, and Green wouldn't find it. Using clever molecular tricks, Green figured out a way to rescue some of the bacteria with defective ribosomes so they could grow.

Chapter 1: How Genes Work

But in many cases, the opportunity exists to learn more about, or possibly even meet, the patient at the other end of the sample. However, most of the figures should be legible, especially in the pdfs. This means that the state in which a baby is born determines the genetic conditions for which he or she will be screened. The yeast cells she uses are the same kind bakeries use to make bread and breweries use to make beer! Over time, mutations supply the raw material from which new life forms evolve see Chapter 3, "Life's Genetic Tree".

While some of the rescued bacteria have changes in their ribosomal RNA that make them resistant to certain antibiotics and thus would not make good antibiotic targets other RNA changes that don't affect resistance may point to promising ideas for new antibiotics. In the human body, one of the most important jobs for proteins is to control how embryos develop. Scientists discovered a hugely important set of proteins involved in development by studying mutations that cause bizarre malformations in fruit flies.

The most famous such abnormality is a fruit fly with a leg, rather than the usual antenna, growing out of its head see photo. According to Thomas C. Kaufman of Indiana University in Bloomington, the leg is perfectly normal—it's just growing in the wrong place. In this type of mutation and many others, something goes wrong with the genetic program that directs some of the cells in an embryo to follow developmental pathways, which are a series of chemical reactions that occur in a specific order. In the antenna-into-leg problem, it is as if the cells growing from the fly's head, which normally would become an antenna, mistakenly believe that they are in the fly's thorax, and therefore ought to grow into a leg.

And so they do. Thinking about this odd situation taught scientists an important lesson—that the proteins made by some genes can act as switches. Switch genes are master controllers that provide each body part with a kind of identification card. If a protein that normally instructs cells to become an antenna is disrupted, cells can receive new instructions to become a leg instead. Scientists determined that several different genes, each with a common sequence, provide these anatomical identification card instructions.

Kaufman isolated and described one of these genes, which became known as Antennapedia , a word that means "antenna feet. Kaufman then began looking a lot more closely at the molecular structure of the Antennapedia gene. In the early s, he and other researchers made a discovery that has been fundamental to understanding evolution as well as developmental biology.

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The scientists found a short sequence of DNA, now called the homeobox , that is present not only in Antennapedia but in the several genes next to it and in genes in many other organisms. When geneticists find very similar DNA sequences in the genes of different organisms, it's a good clue that these genes do something so important and useful that evolution uses the same sequence over and over and permits very few changes in its structure as new species evolve.

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by Ross C. Hardison, 2005

Working with Molecular Genetics. Overview of Part One. Overview of Part One. Genes, Nucleic Acids, Genomes and Chromosomes. Part One of this textbook. Working with Molecular Genetics. by Ross C. Hardison, Professor of Biochemistry, The Pennsylvania State University, University Park.