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Essentials of Medical Genomics Second Edition Stuart M.
Brown(Auth.) Digital Instant Download
Author(s): Stuart M. Brown(auth.)
ISBN(s): 9780470336168, 0470336161
File Details: PDF, 15.18 MB
Year: 2008
Language: english
fm JWBK238/Brown September 4, 2008 11:27 Char Count=
Essentials of
Medical Genomics
fm JWBK238/Brown September 4, 2008 11:27 Char Count=
Essentials of
Medical Genomics
Second Edition
Stuart M. Brown
NYU School of Medicine
New York, NY
with Contributions by
Copyright
C 2009 by John Wiley & Sons, Inc. All rights reserved.
Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s
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Contents
Preface, xi
3 Genome Databases, 53
Genome Sequencing, 53
Entrez, 55
BLAST, 58
Genome Annotation, 59
Genome Browser, 62
Human Genetic Diseases, 66
A System for Naming Genes, 68
Model Organisms (Comparative Genomics), 69
v
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vi Contents
4 Bioinformatics Tools, 79
Patterns and Tools, 79
Sequence Comparison, 82
Multiple Alignment, 86
Pattern Finding, 88
Phylogenetics, 94
Biotechnology Exercise, 97
References, 101
5 Human Genetic Variation, 103
Mutation, 103
Single-Nucleotide Polymorphisms, 107
Linkage, 110
Multigene Diseases, 112
Genetic Testing, 112
SNP Chips, 114
The HapMap Project, 115
Research Uses of SNP Markers, 119
Ethnicity and Genome Diversity, 120
References, 124
Contents vii
8 Microarrays, 179
Spotting versus Synthesis on the Chip, 182
Other Types of Arrays, 187
Differential Gene Expression, 188
Error and Reliability, 195
Evolutionary Perspectives, 197
References, 198
viii Contents
Ribozymes, 268
References, 268
16 Proteomics, 319
Protein Modifications, 320
Quantitative Approaches, 321
Biomarkers, 325
Protein Databases, 330
Protein–Protein Interactions, 331
DNA-Binding Proteins, 334
Structural Proteomics, 335
Drug Targets, 337
References, 337
Contents ix
Glossary, 397
Index, 419
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Preface
xii Preface
STUART M. BROWN
New York
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Anaphase
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FIGURE 1-7. Genes A and B are tightly linked so that they are not separated
by recombination, but gene C is farther away. After recombination occurs in
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ABc, and abC.
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FIGURE 4-1. With computers, it’s easy to find patterns, even if they are not
really there. These letters can be found in butterfly wings. (Kjell B. Sandred,
Butterfly Alphabet, Inc.,Washington, DC.)
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+ =
FIGURE 8-2. Two fluorescent images of a microarray with red and green false
colors combined to show relative gene expression in two samples.
CstF
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Transcribed pre-mRNA
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FIGURE 14-3. A portion of the data display for a whole-genome tiling array.
It was some time before the boys could settle down again to
sleep. Perk often believed he could catch a distant yap from the
ranging hound, and it never failed to give him a thrill. The beast had
seemed both big, and inclined to be savage; and Perk could not help
shuddering to think of his getting loose from his leash and coming
on the cringing lunatic somewhere in the lonely timber.
But finally even the anxious Perk succumbed, and when he again
opened his eyes it was to find that daylight had come, with Elmer
outside starting up the fire, and some one else rattling the tin pans,
as if getting ready for a jolly breakfast.
As that was encroaching on his private preserves, Perk hastened
to bob up and assure the others he would soon be on deck,
prepared to make a mess of his savory “flapjacks,” as he had
solemnly promised to do the very first morning in camp.
Soon every one was busily engaged, for there was bound to be
“heaps” of work laid out for that wonderful day. Amos was
examining the dilapidated roof of the cabin and settling just how
they should go about rendering it waterproof; Wee Willie beat some
batter in a tin vessel, under the eye of the self-constituted master of
ceremonies (for Perk had actually donned a snow-white peakless
cap, fashioned after a regular chef’s headgear, doubtless meaning to
have no dispute regarding his recognized rights to the exalted title);
while Elmer had taken to looking around outside, especially over in
the quarter of the leaning birch tree.
He came over to the fire a little later, and Wee Willie at once
detected indications in his face that made him suspicious.
“You’ve discovered something new, Elmer, now don’t deny it!” he
immediately asserted.
“What is it?” hastily demanded Perk.
“Well,” said Elmer, quietly, “it’s just this; whoever that man may
be, he came back again during the night!”
This information caused all of the others to show fresh interest.
Perk was just in the act of tossing aloft his first flapjack, and in his
nervousness he actually missed connections, so that the delectable
morsel ignominiously fell into the ashes, and was thus lost.
“It wasn’t up to the mark, anyhow,” the nervous cook hastened to
say in apology; “first off the pan shouldn’t be eaten, I always claim.
But you did give me a jolt, Elmer, when you said that.”
“How do you know?” questioned Wee Willie; “run across the sign,
did you?”
“He walked completely around the cabin twice,” stated the other.
“From the indications I’d say he must have been a heap surprised to
discover that it had occupants; for I take it, he could hear some of
us breathing pretty hard.”
“Huh! needn’t all look right at me,” Wee Willie hastened to snap,
as he colored up amidst his freckles. “I made out to lie on my side
the whole live-long night, I’d take my affidavy on that. I admit that
once in a while I do snore; but that’s when I roll over on my back,
and have been gorging at supper on such things as mince pie and
other heavy stuff. Go on, Elmer!”
“I know what you are thinking,” Elmer continued; “how could I
decide that the man didn’t make those marks before we came? I’ll
tell you what proof I have right now. In the first place there isn’t
much dew in the tracks, which I reckon would indicate that the
footprints were made shortly before dawn. Am I right there, Wee
Willie? You’re well up in woodcraft, and ought to be able to say.”
“Sounds good to me,” grunted the other, wagging his head
violently in the affirmative, while a pleased expression on his thin
face told how much he felt complimented by having Elmer defer in
this fashion to his judgment.
“Well, I had another good proof,” Elmer went on to say, with one
of his reassuring smiles. “Where the tracks crossed the marks left by
Collins and his pal they overlapped; that is, this footprint broke into
the ones made by the two guards from the asylum!”
“Splendid work, Elmer!” cried Perk, this time succeeding brilliantly
in tossing up his second flapjack, which alighted successfully in the
pan, with the browned side up. “Guess he did come prowling around
then, and like as not tried the door more’n once. Say, I’m real glad I
fastened it as well as I did.”
“What do you suppose he wanted?” queried Amos, looking even
more serious than was his habit.
“Not being a mind reader,” Elmer told him, “I couldn’t say; but to
make a stab at it I’d guess he hoped we’d gone along, and he could
have his old cabin to himself again.”
“Well, it’ll always be a big mystery who and what this chap can
be,” Wee Willie concluded. “I only hope now he knows we’re
stopping here he’ll take the hint, and keep off the grass. It’ll go
rough with any hobo we catch bothering our traps, let me tell you.
Here, put that one on this warm plate I’ve got on this flat stone
alongside the fire, Perk. It makes a beginning, and we can soon be
starting in to feed.”
“Somebody open that bottle of maple syrup,” observed the
bustling cook a little later on, as another “cart-wheel” cake went
turning over in the air, to be caught dexterously again in the pan.
“And when I get a third one ready you’d better start in eating while
they’re fresh and hot. The coffee’s done; and of course I don’t mean
to commence until somebody can spell me here.”
In good time they were doing full justice to Perk’s famous
flapjacks; which each and every camper solemnly declared when
passing up his pie-tin for more were really unequaled by anything
served at the breakfast table at home.
Of course Wee Willie presently insisted on taking Perk’s place, so
that the chef might take the edge off his own appetite; until finally
all of them declared they could not swallow another bite, and with
three cakes left over.
“For munching on between meals, if any one wants a snack,” Perk
explained, as he put them aside. “Nothing to be wasted in this camp
—that is, except perhaps the first tryout in a batch.”
Then they commenced to do things, each one having jotted down
certain tasks that should be attended to without delay.
Elmer and Wee Willie took upon their shoulders the mending of
the cabin roof; patching up sundry apertures between the logs of
the walls, where the dried mud had long since fallen away through
the action of time and weather combined; and also renewing the
broken hinge on the cumbersome door.
Perk insisted on cleaning up the breakfast things; somehow he
loved to serve in the capacity of cook, and his mates seemed
perfectly willing to have it so, strange to say.
As for Amos, already he had his precious camera out, and
announced his intention of searching the immediate neighborhood,
in hopes of securing some unusual picture.
“I’d like above all things to find a late partridge on her nest,” he
was explaining ere he sauntered forth. “I’ve always wanted to get a
picture of the bird on her eggs, or strutting around with her chicks;
but I’m afraid it’s a heap too late in the season for such a thing to
happen.”
“As a rule the early brood is pretty well grown by now,”
commented Elmer; “still, I remember finding a nest with eggs in it as
late as this, and you might be just lucky enough. Wish you success,
Amos; and if I can help you in any way let me know.”
“Perhaps you may when I get a chance to set a camera trap at
night, so some cunning ’coon, or frisky mink, will take his own
picture. That’s my ambition, you know, Elmer, though I’m not
building my hopes too high, not wanting to be disappointed.”
“I wouldn’t stray too far away, if I were you, Amos,” hinted Wee
Willie.
“Oh! I’m a pretty fair woodsman,” insisted the other, “and I reckon
now the chances of my getting lost are small. But I’ll just wander
around the Bend here, and sort of get my bearings, as well as keep
one eye out for anything that appeals to me.”
“And keep the other on the watch for signs of that tramp, or
lunatic, Amos,” Perk insisted on warning him solicitously.
So Amos walked away, carrying his camera along with him. Elmer
looked after him with an expression akin to concern on his young
face, which shrewd Wee Willie was quick to notice.
“Something seems to be bothering him, don’t you think, Elmer?”
the latter asked in a low tone so that Perk might not hear what he
said.
“Y-es, I’ve thought so myself lately,” admitted Elmer, slowly;
“though you remember, Amos has always been a sobersides of a
chap ever since we came to know him. There’s a sort of family
trouble weighing down on him, I reckon; something that is no one
else’s business. I’d like to comfort him if only I knew how to go
about it; but I don’t want to kick in where outsiders have no right.
But let’s change the subject, Wee Willie; I dislike talking about any
of my chums.”
They worked industriously for an hour and more, and under their
clever tactics the roof began to show decided signs of improvement.
Indeed, already one-half of its surface had been rendered
impervious to water, after the boys had succeeded in thatching it
with bark stripped from certain trees, and overlapping like the
shingles on an ordinary house.
“By the time we get through we needn’t be afraid of the heaviest
kind of a rainfall,” said Elmer, confidently; “unless it’s accompanied
by a fierce wind, such as might strip all this off in a jiffy.”
“Where’s Perk gone?” asked Wee Willie; “I thought I heard him
saying something just then, but it sounded as if he was off
somewhere.”
“I saw him prowling around in the brush yonder ten minutes ago,”
Elmer informed him. “Like as not he’s just bent on seeing if there’s a
good spot for fishing at the Bend here; because, you know Perk
dearly loves to pull in the frisky black bass, or the striped perch, as
well as eat the same.”
“Listen! wasn’t that him speaking again?” hissed Wee Willie,
stopping his task of fastening a strip of pliable bark with small round
tins, through each of which a nail could be driven, such as are used
to secure tarred paper to the roofs of chicken coops and other small
outbuildings.
“No, you don’t, not this time, you nasty thing!” Perk was heard
saying half in disgust, and with a tinge of consternation in his tones.
“Curl up again, and shake your old locust rattle as much as you
please, who cares?”
“Perk!” shouted Elmer excitedly, recognizing a certain dreadful
sound that now floated to his ears, “back away! Don’t fool with a
rattlesnake, you silly! Back water, and in a hurry!”
CHAPTER VI
THE EVENTS OF A DAY
The incident of the climbing black bear was closed around four
that first afternoon in camp. Altogether it had been productive of
considerable excitement, and amusement as well. The day, however,
was fated to see still further singular happenings before closing.
Elmer was inside the cabin “fussing around,” as he called it. He
had cleaned out the shabby old fireplace, making a few badly
needed repairs, so that the chimney might draw properly when they
came to start a blaze there evenings, wishing to gather around, and
chat or sing as the humor seized them.
Amos had wandered off again. He said it seemed to be a banner
day with him so that he felt inclined to roam about and possibly
make a few more discoveries that would be of value; which, of
course, pertained to the camera stunt only—he had thoughts for
nothing else apparently.
Perk and Wee Willie were discussing the menu for supper when
Elmer came out of the cabin door, and approached them. He seemed
to be holding something in his hand, though neither of the other
boys could quite make it out.
“Well,” Elmer commenced saying, as he came up, “I think I’ve
discovered just why our tramp wanted to get back into the cabin
again last night, going all around twice, looking for an opening which
he didn’t find.”
“That sounds interesting,” observed Perk.
“Tell us about it, Elmer,” the tall chum added; “and what under the
sun are you holding there in your hand?”
Elmer laughed softly.
“That’s the answer,” he hastened to say, and then held something
up before their eyes.
“Gee! what a funny knife!” exclaimed Perk.
“Where’d you run across it, Elmer?” demanded Wee Willie.
“The blade is open, you see, just as I found it,” explained the
other. “And it was sticking in a log close by the yawning fireplace.
From the odor that hangs about the blade, I reckon Mr. Tramp must
have used it to slice some plug tobacco, that black, tough kind, you
know, for his old pipe, and then thinking to use it again a little later
on, just stuck it into a log of the wall near his head.”
“Huh! our coming along sent him on the run into the bushes, and
he clean forgot all about his precious old knife—is that what you
mean, Elmer?”
“Just so, Wee Willie; and missing his knife later he started to
come back to recover it. To such men a knife becomes as precious
as—well, Amos’s camera is to him; or your postage-stamp album
might be to you, Perk. Besides, you can see what an odd sort of a
knife this one is.”
“I never saw one like it before,” Perk spoke up. “Why, besides the
one big strong blade it’s got a fork, and a spoon attachment, too.
Fact is, it could be used for a whole meal. Yes, and here’s even a
corkscrew along the back. What a queer knife it is, to be sure! I
don’t wonder the poor old hobo valued it.”
“Perhaps he’s carried it for years and years,” mused Wee Willie,
“and it’s his most treasured possession. I wish he had it in his greasy
pocket again.”
“But see here, boys,” Perk suggested, “how do we know but that
it might have been there for ever so long—mebbe since the cabin
was in use before that tragedy happened here, that I’ve heard the
folks down Chester way mention?”
Elmer and the tall chum exchanged meaning glances. They had
supposed that Perk knew nothing about that tragic event, and had
agreed to “keep mum” about it while in camp at Log Cabin Bend,
lest he feel uneasy.
“Oh! that’s an easy thing to decide, Perk,” the former assured him.
“If you examine the blade you’ll find it’s clear of rust, though far
from bright. Now that couldn’t be the case if it had been exposed
here for years to the damp air, such as would blow into the cabin
with the door swung half-way open most of the time it’s stood
empty.”
“I get you, Elmer; please excuse my dense ignorance,” said Perk
hurriedly. “Now I wonder whether he’s going to keep on hanging out
around here until he gets back his old knife?”
“We’ll have to put out a sign, and invite the chap to step up to the
captain’s office and prove property,” Wee Willie argued whimsically
after his fashion. “No questions asked, and no reward expected for
finding the lost trusty blade; only we’d like him to clear out, and
leave us alone. I’ve seen a bunch of tramps, and a mussy lot they
are, taken as a whole. I always try to get to windward of ’em when
watching how they manage to cook a meal in tomato-cans and
such.”
“But we saw no sign of his having had a fire in the cabin,” Perk
went on to remark, reflectively; “and there wasn’t the first evidence
of his having made a bed out of brush. How do you account for that,
Elmer?”
“Oh! he may have arrived only an hour before we did, and was so
tired he just lay down to smoke and rest,” came the ready answer;
for Elmer always seemed to have a faculty for meeting objections.
“What will you do with it?” continued Perk.
“I haven’t decided,” Elmer told him. “I may hit on a way to get it
back into the possession of the owner without hunting him up.
Leave that to me.”
“There’s Amos coming along,” Wee Willie added; “somehow he
seems to be looking a whole lot happier than this morning. It must
have been his success at snapping off the bear in the beechnut
tree.”
“Yes, that was what did it,” Elmer agreed; though his brow
clouded, for this unexplained mystery that seemed to be always
hanging over his comrade, making him so unhappy, was beginning
to worry him considerably; he wanted to be of service to Amos, yet
could not muster up courage to break in upon the other’s reserve,
since it would seem so much like thrusting himself into business that
did not at all concern him.
Amos was actually smiling as he approached, and few of the
Chester boys could truly say they had ever seen such a genuine look
of delight on his sad face.
“What do you think?” he burst out, excitedly, “I managed to get a
glimpse of Mr. Mink, the very first of his kind I ever had the luck to
see alive! Oh! but he’s a slick article, let me tell you, with his beady
little eyes, and soft furry hide. And I planned it all out just where we
ought to set the camera-trap to-night, Elmer, so’s to coax him to pull
the cord, and set the flashlight going.”
Elmer looked at him with affection. Somehow he had come to
care a great deal for Amos, which in one way was rather strange; for
to most of the fellows the newcomer in Chester had not appealed at
all, owing to his being such a moody fellow. But as is usually the
case with such serious persons, when his face did light up in a smile
it was wonderfully “fetching.”
“I reckon we’ll manage to get a picture of his Highness, King
Mink,” Elmer assured him; “when we’ve laid ourselves out to the
limit. I know a few tricks along those lines, which are quite at your
service, Amos. But see here, what a queer find I made in the old
cabin.”
He held up the quaint pocket-knife as he said this, and the eyes of
the other became instantly focussed on it. To the astonishment,
almost consternation, of Elmer, he seemed to be immediately
strongly affected by the sight of the late property of the roving
tramp.
Perk and Wee Willie also stared to notice how the face of Amos,
actually showing a dash of color when he first joined them, now
suddenly became as pale as that of a ghost. His breath came and
went in gasps, though apparently he was making desperate efforts
to hold himself within bounds, doubtless realizing how his startled
companions must be observing him.
“Where did you say you found it, Elmer?” he finally managed to
say, in what might be termed half gasps, while he could be seen
swallowing something that seemed to rise in his throat, and threaten
to choke him, poor fellow.
“Why, in the cabin there,” explained the other, hesitatingly. “It was
sticking in one of the logs forming the wall, between the little
opening used as a window and the big fireplace. I think the hobo
must have used it to cut up some hard plug tobacco, for it smells
rank of the stuff; and then carelessly thrust the point into the log,
before our coming frightened him away.”
“And, what do you think,” Perk now managed to add, “Elmer
believes it was to recover this old knife that the old tramp came back
and walked around the cabin twice last night, looking for a chance to
get inside. Too bad, isn’t it, Amos?”
Amos, however, seemed to pay scant attention to what Perk was
saying. His distended eyes were fastened on the article which still lay
exposed in Elmer’s open palm.
“But—couldn’t it have been there a long time, don’t you think?” he
now asked, as though clinging to a straw; “say as much as—six or
seven years?”
“I’m dead sure it hasn’t,” he was told positively. “In the first place,
other persons besides us have visited the old cabin here from time
to time, and some one would surely have found it. Then again, look
how smooth the steel of the discolored blade is; it must have rusted
if it had been exposed to the weather for even a few months. Oh!
no, Amos, whoever the tramp is, he surely put it where I found it,
and this very night.”
“I—guess you’re right, Elmer,” fell in trembling tones from the lips
of the other, still looking peaked and white. “W—would you mind my
looking at it?”
“Certainly not,” said Elmer, at the same time thrusting the queer
knife into the other’s hand, eagerly stretched out to receive it.
All of them could not help but notice how his hand trembled
violently from some sort of emotion as the fingers closed about the
haft of the knife. Evidently there was some element about the find of
Elmer that affected Amos Codling. He turned the knife over, and
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