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Genetics And You: Nursery Genetics

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 1960s in Massachusetts with testing for PKU, a disease affecting 1 in 14,000 people. PKU is caused by an enzyme that doesn’t work properly due

to a genetic muta­ tion. 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 neurolog­ ical 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 advo­ cated 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.

In 2006, the Advisory Committee on Heritable Disorders in Newborns

and Children, which assists the Secretary of the U.S. 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.
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 state­of­the­art just a few years ago, this kind of analysis would have taken hundreds of years.

After demonstrating that his technique worked in yeast, Young then took his research a step forward. He used a variation of the yeast

A ribosome consists of large and small protein subunits with transfer RNAs nestled in the middle. 

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 tran­ scribed correctly in people with the disease.
This information provides researchers with an important tool for understanding how dia­ betes 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 jump­start genes on demand, change the course of a disease or prevent it from ever happening.

Found in Translation

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. As the messenger RNA threads through the ribosome protein machine, the ribosome reads the mRNA sequence and helps recognize and recruit the correct amino acid­ carrying transfer RNA to match the mRNA code. The ribosome also links each additional amino acid into a growing protein chain (see drawing, page 13). 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. Sidney Altman of Yale University in New Haven, Connecticut, and Thomas Cech, who was then at the University of Colorado in Boulder, each discovered that RNA can perform work as complex as that done by protein enzymes. Their “RNA­as­an­enzyme” discovery turned the research world on its head and earned Cech and Altman the 1989 Nobel Prize in chemistry. Noller and other researchers have continued the painstaking work of understanding ribo­ somes. In 1999, 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.

RNA Surprises

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. 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 impor­ tant for learning how to disrupt the actions of disease­causing 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. 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.

An Interesting Development

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 study­ ing 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 page 21). 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 antenna­into­leg 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 1980s, he and other researchers made a discovery that has been fundamental to understanding evolution as well as developmental biology. 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. Researchers quickly discovered nearly identical versions of homeobox DNA in almost every non­bacterial cell they examined—from yeast to plants, frogs, worms, beetles, chickens, mice and people. Hundreds of homeobox­containing genes have been identified, and the proteins they make turn out to be involved in the early stages of development of many species. For example, researchers have found that abnormalities in the homeobox genes can lead to extra fingers or toes in humans.

The Tools of Genetics: Mighty Microarrays

We now have the ability to attach a piece of every gene in a genome (all of an organism’s genes) to a postage stamp­sized glass microscope slide. This ordered series of DNA spots is called a DNA microarray, a gene chip or a DNA chip. Whichever name you prefer, the chip could also be called revolutionary. This technology has changed the way many geneticists do their work by making it possible to observe the activity of thousands of genes at once. In recent years, microarrays have become standard equipment for modern biologists,but teachers and students are using them, too. The Genome Consortium for Active Teaching program ( pro­ vides resources and instructions for high school and college students to do gene­chip experiments in class. Microarrays are used to get clues about which genes are expressed to control cell, tissue or organ function. By measuring the level of RNA production for every gene at the same time, researchers can learn the genetic programming that makes cell types different and diseased cells different from healthy ones. The chips consist of large numbers of DNA fragments distributed in rows in a very small space. The arrays are laid out by robots that can
position DNA fragments so precisely that more than 20,000 of them can fit on one micro­ scope slide. Scientists isolate mRNA from cells grown under two conditions and tag the two sources of RNA with different colors of fluorescent mole­ cules. The two colors of RNA are then placed on the chip, where they attach to complementary DNA fragments anchored to the chip’s surface. Next, a scanner measures the amount of fluorescence at each spot on the chip, revealing how active each gene was (how much mRNA each gene produced). A computer analyzes the patterns of gene activity, providing a snapshot of a genome under two conditions (e.g., healthy or diseased). In December 2004, the U.S. Food and Drug Administration cleared the first gene chip for medical use. The Amplichip CYP450™, made by Roche Molecular Systems Inc. of Pleasanton, California, analyzes varia­ tions in two genes that play a major role in the body’s processing of many widely pre­ scribed drugs. This information can help doctors choose the proper dose of certain medicines for an individual patient
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