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Graveyard Shift (SpongeBob SquarePants)
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"Graveyard Shift"
SpongeBob SquarePants episode
Title card
Episode no.
Season 2
Episode 16a (36a)
Directed by
Nick Jennings (art)
Sean Dempsey (animation)
Jay Lender (storyboard)
Dan Povenmire (storyboard)
Alan Smart (supervising)
Written by
Mr. Lawrence
Jay Lender
Dan Povenmire
Original air date
September 6, 2002 (2002-09-06)
Episode chronology
← Previous
"Band Geeks" Next →
"Krusty Love"
SpongeBob SquarePants (season 2)
List of SpongeBob SquarePants episodes
"Graveyard Shift" is the first part of the 16th episode of the second season, and the 36th episode overall, of the American animated television series SpongeBob SquarePants. The episode was written by Mr. Lawrence, Jay Lender and Dan Povenmire, and the animation was directed by Sean Dempsey. Lender and Povenmire also served as storyboard directors. It originally aired on Nickelodeon in the United States on September 6, 2002, one year after "Band Geeks".
The series follows the adventures and endeavours of the title character and his various friends in the underwater city of Bikini Bottom. In this episode, Squidward and SpongeBob are forced to work 24 hours a day by Mr. Krabs, so that he can get more money. Squidward soon gets bored, and tells SpongeBob a scary story to have some fun with him. After scaring SpongeBob, Squidward tells him that the story is fictional. However, when Squidward and SpongeBob are alone, the events in Squidward's story begin to occur.
The episode featured stock footage of Max Schreck as Count Orlok from the 1922 silent film Nosferatu. Episode writer Lender proposed the idea as a gag at the end of the episode, which series creator Stephen Hillenburg accepted. Before the idea of Count Orlok, Lender thought of "Floorboard Harry", an idea that was deleted. The episode received critical acclaim upon release.
Contents
[hide]
1 Plot
2 Production
3 Reception
4 References
5 External links
Plot[edit]
The episode begins with Squidward eagerly preparing to leave work at the Krusty Krab. Moments before he can leave, however, a customer shows up asking to be served. When the customer says that he will come to the Krusty Krab if it stays open later, Mr. Krabs is inspired to create a night shift, leaving an anticipating SpongeBob and an annoyed Squidward to work 24-hour shifts.
Exasperated with his boss's demands and annoyed by SpongeBob's eagerness, Squidward tries to scare SpongeBob into being afraid of the night shift by telling him a made-up story about the "Hash-Slinging Slasher", a former fry cook at the Krusty Krab who accidentally cut off his own arm and was run over by a bus during the night shift, causing his death. Squidward continues by telling SpongeBob that every Tuesday night (the night it happens to be) the ghost of the Slasher returns to the Krusty Krab. Squidward says that the Slasher's arrival will be indicated by three warnings: the lights flickering on and off, the phone ringing but nobody being on the other line, and the ghost of the bus that killed the Slasher arriving to deliver him.
Although Squidward, annoyed with SpongeBob's fear at the story, manages to convince him that he made the whole story up, the two are soon alarmed by strange occurrences that parallel the omens that signify the arrival of the Hash-Slinging Slasher later that night when the restaurant is empty. Although convinced at first that these occurrences are coincidence, Squidward grows more nervous as the occurrences continue.
Finally, at the end, a bus shows up outside the Krusty Krab, despite Squidward claiming that the buses do not run this late at night. The bus then drops off a mysterious dark silhouette matching the description of the Hash-Slinging Slasher. SpongeBob and Squidward immediately realize that they are experiencing genuine supernatural events and panic. When the strange, unidentified figure enters the building, it is revealed he is simply a kid applying for a job, stating that he had tried calling the Krusty Krab by telephone earlier, but had hung up out of nervousness (the bus that he arrived in remains unexplained). However, Squidward then questions who was flickering the lights earlier. It is then revealed that the flickering lights are caused by doctored footage of Count Orlok from the 1922 silent film Nosferatu, with whom the characters are inexplicably familiar, flicking the light switch on and off.
Production[edit]
Original sketch of a deleted scene by Jay Lender, in which SpongeBob is delivering mail to Floorboard Harry.
"Graveyard Shift" was written by Mr. Lawrence, Jay Lender, and Dan Povenmire, with Sean Dempsey serving as animation director. Lender and Povenmire also served as storyboard directors.[1][2] The episode originally aired on Nickelodeon in the United States on September 6, 2002, with a TV-Y7 parental rating.[3]
Episode writer Lender proposed to have Count Orlok of the 1922 silent film Nosferatu appear as a gag at the end of the episode.[4] Series creator Stephen Hillenburg accepted Lender's proposal and allowed him to do it.[4] Lender said, "Steve gave you the opportunities to do things that would really be memorable, if you could sell him on it."[4] Lender then searched for books with scannable pictures of Count Orlok.[4] However, the image of Count Orlok used in the episode was taken from the Internet.[4] He said, "I searched what little there was of the Web back then."[4] Nick Jennings Photoshopped the smile on Count Orlok to make sure it matched Lender's board drawing.[4] Lender said, "It was my baby, and I held its hand until we shipped it overseas [to Rough Draft Studios in South Korea]."[4] Before his idea of Count Orlok, Lender thought of "Floorboard Harry",[4] a deleted gag that concludes the broadcast episode, in which he initially flickers the lights.[4]
"Graveyard Shift" was released on the DVD compilation titled SpongeBob SquarePants: Nautical Nonsense and Sponge Buddies on March 12, 2002.[5][6][7] It was also included on the SpongeBob SquarePants: The Complete 2nd Season DVD released on October 19, 2004.[8][9] On September 22, 2009, the episode was released on the SpongeBob SquarePants: The First 100 Episodes, alongside all of the episodes of seasons one through five.[10][11] On September 14, 2010, "Graveyard Shift" was released on the SpongeBob SquarePants: 10 Happiest Moments DVD.[12][13][14][15]
Reception[edit]
"Graveyard Shift" received critical acclaim upon release and is often cited as one of the show's best episodes. Emily Esteem of WeGotThisCovered.com ranked the episode No. 2 on her "Top 10 Episodes of SpongeBob SquarePants" list, saying, "[It] is another scary episode of SpongeBob, and it's my favorite one."[16] She added, "I love 'Graveyard Shift' for a myriad of reasons, but mostly because it puts the two SpongeBob SquarePants characters with the best chemistry together: Squidward and SpongeBob. The episode is kind of like a puzzle, and SpongeBob's relentless cheer in the midst of likely doom is inspiring."[16]
In his review for the DVD Talk, Jason Bovberg praised the episode for its "spooky wonderfulness",[9] stating that the episode scared his daughter.[9] Paul Mavis of DVD Talk said, "A fun, 'scary' (for little kids) SpongeBob that adults will appreciate, 'Graveyard Shift' uses the old standby of the headless/handless/legless (take your pick) killer-seeking-revenge stories we all told as kids, and cleverly grafts it onto a 'SpongeBob at work' storyline."[17] Mavis added, "I always enjoy it when Rodger Bumpass, the voice actor for Squidward, gets quiet and manipulative when he's shining SpongeBob on, and here's one of the best examples of that."[17] He praised Count Orlok's cameo, "especially when they animate the vampire's face into a goofy, giddy smile."[17] Mike Jackson of DVD Verdict said the episode is one of his "personal faves."[18] He also said "[The episode] has everything that makes the show great: funny dialogue (the whole story of the Hash-Slinging Slasher is hilarious), clever sight gags (especially SpongeBob's regenerating limbs), and that aforementioned outta-nowhere ending that made me bust a gut."[18]
References[edit]
Jump up ^ SpongeBob SquarePants: The Complete 2nd Season ("Graveyard Shift" credits) (DVD). United States: Paramount Home Entertainment/Nickelodeon. October 19, 2004.
Jump up ^ Lender, Jay. "SpongeBob SquarePants". JayLender.com. Retrieved September 1, 2013.
Jump up ^ "SpongeBob SquarePants : The Graveyard Shift; Krusty Love". Zap2it. Retrieved September 2, 2013.
^ Jump up to: a b c d e f g h i j Heintjes, Tom (September 21, 2012). "The Oral History of SpongeBob SquarePants". Hogan's Alley. Retrieved September 1, 2013.
Jump up ^ SpongeBob SquarePants: Nautical Nonsense and Sponge Buddies. DVD. Paramount Home Entertainment, 2004.
Jump up ^ Bovberg, Jason (April 15, 2002). "SpongeBob Squarepants: Nautical Nonsense and Sponge Buddies". DVD Talk. Retrieved September 1, 2013.
Jump up ^ Lacey, Gord (March 8, 2002). "SpongeBob SquarePants - Nautical Nonsense/ Sponge Buddies Review". TVShowsOnDVD.com. Retrieved September 1, 2013.
Jump up ^ SpongeBob SquarePants: The Complete 2nd Season. DVD. Paramount Home Entertainment, 2004.
^ Jump up to: a b c Bovberg, Jason (October 11, 2004). "SpongeBob SquarePants: The Complete Second Season". DVD Talk. Retrieved September 1, 2013.
Jump up ^ SpongeBob SquarePants: The First 100 Episodes. DVD. Paramount Home Entertainment, 2009.
Jump up ^ Lacey, Gord (September 29, 2009). "SpongeBob SquarePants - The First 100 Episodes (Seasons 1-5) Review". TVShowsOnDVD.com. Retrieved September 1, 2013.
Jump up ^ SpongeBob SquarePants: 10 Happiest Moments. DVD. Paramount Home Entertainment, 2010.
Jump up ^ Basile, Nancy. "'SpongeBob SquarePants: 10 Happiest Moments'". About.com. Retrieved September 1, 2013.
Jump up ^ "SpongeBob SquarePants: 10 Happiest Moments". KidzWorld.com. Retrieved September 1, 2013.
Jump up ^ Pritchard, Paul (September 9, 2010). "SpongeBob Squarepants: 10 Happiest Moments". DVD Verdict. Archived from the original on September 22, 2013. Retrieved September 1, 2013.
^ Jump up to: a b Estep, Emily (December 5, 2011). "Top 10 Episodes Of Spongebob Squarepants". WeGotThisCovered.com. Retrieved September 1, 2013.
^ Jump up to: a b c Mavis, Paul (September 16, 2010). "SpongeBob SquarePants: 10 Happiest Moments". DVD Talk. Retrieved September 1, 2013.
^ Jump up to: a b Jackson, Mike. "Spongebob Squarepants: Nautical Nonsense / Sponge Buddies". DVD Verdict. Archived from the original on September 22, 2013. Retrieved September 1, 2013.
External links[edit]
SpongeBob SquarePants portal
Nickelodeon portal
Wikiquote has quotations related to: "Graveyard Shift"
"Graveyard Shift" on IMDb
"Graveyard Shift" at TV.com
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The High Chaparral
From Wikipedia, the free encyclopedia
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The High Chaparral
Genre
Western
Created by
David Dortort
Starring
Leif Erickson
Cameron Mitchell
Mark Slade
Henry Darrow
Linda Cristal
Don Collier
Theme music composer
David Rose
Composer(s)
Harry Sukman
Country of origin
United States
Original language(s)
English
No. of seasons
4
No. of episodes
98 (list of episodes)
Production
Running time
60 minutes
Production company(s)
Xanadu Productions in association with NBC
Distributor
Republic Pictures
Worldvision Enterprises
CBS Television Distribution
NBCUniversal Television Distribution
Release
Original network
NBC
Original release
September 10, 1967 (1967-09-10) – March 12, 1971 (1971-03-12)
Guest star Barbara Hershey and Mark Slade
The High Chaparral is an American Western-themed television series starring Leif Erickson and Cameron Mitchell, which aired on NBC from 1967 to 1971. The series, made by Xanadu Productions in association with NBC Productions, was created by David Dortort, who had previously created Bonanza for the network. The theme song was also written and conducted by Bonanza scorer David Rose, who also scored the two-hour pilot.
Contents
[hide]
1 Cast and characters
2 Series format
2.1 Name of the ranch
3 Production
4 Syndication
5 DVD
6 Episodes
7 See also
8 References
9 External links
Cast and characters[edit]
The show revolves around "Big John" Cannon (Leif Erickson), a rancher living in the Arizona Territory in the 1870s. He runs the ranch, called The High Chaparral, with his brother Buck (Cameron Mitchell) and son Billy Blue (known as Blue Boy) (Mark Slade). Blue Boy's mother, Annalee (Joan Caulfield), is killed in the first episode by an Indian arrow, and John Cannon then marries Victoria (Linda Cristal), the daughter of powerful neighboring rancher Don Sebastián Montoya (Frank Silvera), in what is initially a marriage of convenience. His marriage to Victoria also brings her brother Manolito (Henry Darrow) to live with the family.
Among the guest stars were Rico Alaniz, Richard Bradford, Scott Brady, Anthony Caruso, Chief Dan George, Roberto Contreras, Dennis Cross, Jim Davis, John Dehner, Charles Durning, Paul Fix, Steve Forrest, Ron Foster, Frank Gorshin, Ron Hagerthy, Ron Hayes, Myron Healey, Barbara Hershey, Don Keefer, Dan Kemp, Robert Loggia, Jack Lord, Tyler McVey, Ricardo Montalban, Joanna Moore, Nehemiah Persoff, Stuart Randall, Gilbert Roland, Ned Romero, Kurt Russell, Frank Silvera, Barry Sullivan, William Sylvester, William Tannen, Dub Taylor, Denver Pyle, Paul Winfield, and Morgan Woodward.
Series format[edit]
The two-hour opening episode establishes the background to the action, bringing John Cannon and his family to Arizona, where they buy a run-down hacienda and establish a cattle ranch on it. The Apache Indians, under the leadership of Cochise, are hostile; John's wife is killed in an attack, and in order to survive the Cannons are compelled to enter into an alliance with a rich and powerful neighboring rancher, Don Sebastian Montoya, who owns a huge estate on the Mexican side of the border adjoining the High Chaparral.
Part of the price for the alliance is the sealing of the pact by the marriage of John Cannon to Montoya's daughter, Victoria. Montoya's feckless son, Manolito, whose relationship with his father is strained, accompanies his sister in order to get away from Don Sebastian. John's son, Blue, is vehemently opposed to the marriage, coming so soon after Anna-Lee's death.
Reinforced by Montoya's men, the Cannons are able to fight off the Indian attacks, and, with the services of Manolito as interpreter, manage to negotiate a truce, albeit a fragile one, with the Apache leader. The main reason for its fragility is that the US Cavalry refuses to recognize Cannon's right to negotiate a peace with the Apaches, and continued Army interference constantly threatens the treaty. There are also frequent problems between the Cannons and the arrogant Don Sebastian, usually concerning the terms of their alliance.
Big John's brother, Buck, notionally the ranch's head cowhand, was a hard-bitten former soldier, who fought in the American Civil War, ten years previously, on the side of the Confederacy. From time to time Buck's past came back to haunt him, usually in the person of other Confederate soldiers drifting through the Territory, forever unable to return to their homes in the defeated South. Occasionally, there was friction as a result of the fact that Big John had also fought in the war, but on the other side, as a Captain in the Union Army.
The series gradually evolved to make Manolito and Buck the most popular characters, as they were the ones who tended to get into trouble; both were somewhat irresponsible, particularly under the influence of drink. The other characters were gradually marginalised. Cattle ranching almost never featured in the storylines, which, whenever there were no imminent Indian troubles, were much more likely to revolve around Manolito or Buck and some form of hell-raising - gambling, women, or whiskey.
Mark Slade (Blue-boy) did not appear in the final season and Frank Silvera (Don Sebastian) had died while the series was still in production (but he did appear in a couple of episodes). Blue-boy was replaced by Wind, a new cowhand who was half-Indian and of a similar age to Blue, and who sometimes acted as a go-between for the ranchers and the Indians. This final season had new opening titles and a rearranged version of the theme tune.
Name of the ranch[edit]
The name was explained by the following dialog in Episode 1:
Annalee Cannon: Isn't it beautiful, John? It should have a name.
Big John Cannon: You name it.
Annalee Cannon: What is that bush called — that green one?
Big John Cannon: Chaparral.
Annalee Cannon: That's it — Chaparral. I christen thee "The High Chaparral" — the greatest cattle ranch in the whole territory ... the whole world!
In the true sense of the word, "chaparral," is not a single species of shrub but a bionomic community of desert flora located near a coast especially that in coastal California. There is also some colloquial use of the term in Arizona to describe the low growing Sage, Mesquite and Palo Verde growing there especially in the higher deserts. But the high Sonoran Desert Arizona plant community is more properly called a "xeric" shrublands biome.
Production[edit]
The High Chaparral was Dortort's brainchild, and he left the day-to-day running of Bonanza in the spring of 1967 so he could focus all of his energies on The High Chaparral. After the show's cancellation in 1971, Dortort chose not to return to Bonanza and retired.[citation needed]
All the exterior filming was done at Old Tucson Studios in Arizona and in the nearby Saguaro National Park, although in a few later episodes there was some filming in California and (in season 3) in the Coronado National Forest south of Tucson. The interiors were generally filmed at the NBC television studios in Burbank, Los Angeles.[1]
Cameron Mitchell was offered the part of Buck following an airline flight to Tucson where he sat next to the series creator and his wife.[citation needed]
Syndication[edit]
The series has appeared on CBN, The Family Channel, Hallmark Channel, INSP and, as of August 28, 2017, on Heroes & Icons.
DVD[edit]
On May 20, 2010 the first worldwide release of season 1 on DVD occurred in Germany (Kinowelt, now Studiocanal), with subtitles in English and dubbed into German. Season 2 was released on December 9, 2010. Season 3 was released June 9, 2011. The final season 4 was released in February 16, 2012. On disc 1 episode 1 starts with some scenes shown on German TV that were not in the original and thus dubbed German instead of English for a few minutes.
Art-S Home Entertainment (www.art-s.nl) in the Netherlands released the first box with season 1 (28 episodes) on May 2, 2012. Season 2 released on January 28, 2013. Season 3 released on September 3, 2013 and the final season 4 released January 26, 2014. The High Chaparral is also released in Sweden with each season in 2 boxes. In Australia they have also released The High Chaparral in 4 boxes.
Season
Episodes
Region 1
Region 2
Germany
Region 2
Netherlands
Region 2
Sweden
Region 4
Chile
Region 4
Australia
Season 1 28 May 20, 2010 May 2, 2012 October 30, 2012 November, 2012 March 13, 2013
Season 2 26 December 9, 2010 January 28, 2013 March 19, 2013 December, 2012 May 8, 2013
Season 3 26 June 9, 2011 September 3, 2013 July 31, 2013 January, 2013 August 7, 2013
Season 4 18 February 16, 2012 January 26, 2014 October 8, 2013 February, 2013 January 15, 2014
Episodes[edit]
Main article: List of The High Chaparral episodes
See also[edit]
High Chaparral Theme Park (Sweden)
References[edit]
Jump up ^ Lightning in a Bottle, autobiography of Henry Darrow
https://www.amazon.com/s/ref=nb_sb_noss?url=search-alias%3Daps&field-keywords=+Lightning+in+a+Bottle%2C+autobiography+of+Henry+Darrow
External links[edit]
Wikimedia Commons has media related to The High Chaparral.
The High Chaparral Home Page
The High Chaparral & Bonanza FanFiction
The High Chaparral on IMDb
The High Chaparral Reunion
Retrieved from "https://en.wikipedia.org/w/index.php?title=The_High_Chaparral&oldid=835483695"
Categories:
Western (genre) television series
NBC network shows
1960s American television series
1970s American television series
Television series by CBS Television Studios
1967 American television series debuts
1971 American television series endings
Television shows set in Arizona
Television shows set in Tucson, Arizona
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Indian Accounting Standards
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Indian Accounting Standard (abbreviated as Ind-AS) is the Accounting standard adopted by companies in India and issued under the supervision and control of Accounting Standards Board (ASB), which was constituted as a body in the year 1977. ASB is a committee under Institute of Chartered Accountants of India (ICAI) which consists of representatives from government department, academicians, other professional bodies viz. ICAI, representatives from ASSOCHAM, CII, FICCI, etc.
The Ind AS are named and numbered in the same way as the corresponding International Financial Reporting Standards (IFRS). National Advisory Committee on Accounting Standards (NACAS) recommend these standards to the Ministry of Corporate Affairs (MCA). MCA has to spell out the accounting standards applicable for companies in India. As on date MCA has notified 41 Ind AS. This shall be applied to the companies of financial year 2015-16 voluntarily and from 2016-17 on a mandatory basis.
Based on the international consensus, the regulators will separately notify the date of implementation of Ind-AS for the banks, insurance companies etc. Standards for the computation of Tax has been notified as ICDS in February 2015.[1]
Contents
[hide]
1 History
2 Applicability[2][3][4][5]
2.1 Mandatory Applicability from Accounting Period beginning on or after 1st April 2016
2.2 Mandatory Applicability from Accounting Period beginning on or after 1st April 2017
3 List of Indian Accounting Standards[6]
4 Provisions
5 See also
6 References
History[edit]
India was following accounting standards from Indian Generally Acceptable Accounting Principle (IGAAP) prior to adoption of the Ind-AS.[2][3]
Applicability[2][3][4][5][edit]
Companies shall follow Ind AS either Voluntarily or Mandatorily. Once a company follows Indian AS, either mandatorily or voluntarily, it can't revert to old method of Accounting.
Mandatory Applicability from Accounting Period beginning on or after 1st April 2016[edit]
Every Company with Net worth of not less than ₹5 billion ($73.4 million or 500 crs).
Mandatory Applicability from Accounting Period beginning on or after 1st April 2017[edit]
Every Listed Company.
Unlisted Companies with Net Worth of not less than ₹ 2.5 billion ($36.7 million) and not more than ₹ 5 billion ($73.4 million).
List of Indian Accounting Standards[6][edit]
Ind As No.
Name of Indian Accounting Standard
Ind AS 101 First-time adoption of Ind AS
Ind AS 102 Share Based payments
Ind AS 103 Business Combination
Ind AS 104 Insurance Contracts
Ind AS 105 Non-Current Assets Held for Sale and Discontinued Operations
Ind AS 106 Exploration for and Evaluation of Mineral Resources
Ind AS 107 Financial Instruments: Disclosures
Ind AS 108 Operating Segments
Ind AS 109 Financial Instruments
Ind AS 110 Consolidated Financial Statements
Ind AS 111 Joint Arrangements
Ind AS 112 Disclosure of Interests in Other Entities
Ind AS 113 Fair Value Measurement
Ind AS 114 Regulatory Deferral Accounts
Ind AS 115 Revenue from Contracts with Customers
Ind AS 1 Presentation of Financial Statements
Ind AS 2 Inventories
Ind AS 7 Statement of Cash Flows
Ind AS 8 Accounting Policies, Changes in Accounting Estimates and Errors
Ind AS 10 Events after Reporting Period
Ind AS 11 Construction Contracts
Ind AS 12 Income Taxes
Ind AS 16 Property, Plant and Equipment
Ind AS 17 Leases
Ind AS 18 Revenue
Ind AS 19 Employee Benefits
Ind AS 20 Accounting for Government Grants and Disclosure of Government Assistance
Ind AS 21 The Effects of Changes in Foreign Exchange Rates
Ind AS 23 Borrowing Costs
Ind AS 24 Related Party Disclosures
Ind AS 27 Separate Financial Statements
Ind AS 28 Investments in Associates and Joint Ventures
Ind AS 29 Financial Reporting in Hyper inflationary Economies
Ind AS 32 Financial Instruments: Presentation
Ind AS 33 Earnings per Share
Ind AS 34 Interim Financial Reporting
Ind AS 36 Impairment of Assets
Ind AS 37 Provisions, Contingent Liabilities and Contingent Assets
Ind AS 38 Intangible Assets
Ind AS 40 Investment Property
Ind AS 41 Agriculture
Provisions[edit]
Ind-AS is in line with the International Financial Reporting Standards (IFRS).[7]
Ind-AS 107 deals with disclosures related to financial instruments and related risks and the policies for managing such risks.[4]
See also[edit]
Nepal Financial Reporting Standards
References[edit]
Jump up ^ "Indian Accounting Standards Converged with IFRS Notified". Press Information Bureau.
^ Jump up to: a b "How new accounting standards will impact Indian companies", The Economic Times, 14 July 2016
^ Jump up to: a b "Ind-AS to raise June quarter tax liabilities by 20%", The Economic Times, 13 April 2016
^ Jump up to: a b "Ind AS requires 3,000 disclosures for fair picture of cos", Business Standard, 24 May 2016
Jump up ^ "Company (Inaian Accounting Standard) Rules, 2015" (PDF).
Jump up ^ "Ministry Of Corporate Affairs - Indian Accounting Standards". www.mca.gov.in. Retrieved 2017-01-21.
Jump up ^ "Corporates put restructuring, mergers, de-mergers within organisation on hold", The Economic Times, 27 May 2016

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Cell-free fetal DNA
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Cell-free fetal DNA (cffDNA) is fetal DNA which circulates freely in the maternal blood. Maternal blood is sampled by venipuncture. Analysis of cffDNA is a method of non-invasive prenatal diagnosis frequently ordered for pregnant women of advanced maternal age.
Contents
[hide]
1 Background
2 Laboratory methods
2.1 Separation of cffDNA
2.2 Analysis of cffDNA
2.2.1 Quantitative real-time PCR
2.2.2 Nested PCR
2.2.3 Digital PCR
2.2.4 Shotgun sequencing
2.2.5 Mass spectrometry
2.2.6 Epigenetic modifications
2.2.7 mRNA
3 Applications
3.1 Prenatal sex determination
3.2 Single gene disorders
3.3 Hemolytic disease of the fetus and newborn
3.4 Aneuploidy
3.5 Preeclampsia
4 Future perspectives
5 See also
6 References
Background[edit]
Cell free fetal DNA sheds into the maternal blood circulation
cffDNA originates from placental trophoblasts.[1][2] Fetal DNA is fragmented when placental microparticles are shed into the maternal blood circulation (figure 1).[3]
cffDNA fragments are approximately 200 base pairs (bp) in length. They are significantly smaller than maternal DNA fragments.[4] The difference in size allows cffDNA to be distinguished from maternal DNA fragments.[5][6]
Approximately 11 to 13.4 percent of the cell-free DNA in maternal blood is of fetal origin. The amount varies widely from one pregnant woman to another.[7] cffDNA is present after five to seven weeks gestation. The amount of cffDNA increases as the pregnancy progresses.[8] The quantity of cffDNA in maternal blood diminishes rapidly after childbirth. Two hours after delivery, cffDNA is no longer detectable in maternal blood.[9]
Analysis of cffDNA may provide earlier diagnosis of foetal conditions than current techniques. As cffDNA is found in maternal blood, sampling carries no associated risk of spontaneous abortion.[10][11][12][13][14] cffDNA analysis has the same ethical and practical issues as other techniques such as amniocentesis and chorionic villus sampling.[15]
Some disadvantages of sampling cffDNA include a low concentration of cffDNA in maternal blood; variation in the quantity of cffDNA between individuals; a high concentration of maternal cell free DNA compared to the cffDNA in maternal blood.[16]
New evidence shows that cffDNA test failure rate is higher, fetal fraction (proportion of fetal versus maternal DNA in the maternal blood sample) is lower and PPV for trisomies 18, 13 and SCA is decreased in IVF pregnancies compared to those conceived spontaneously.[17]
Laboratory methods[edit]
A maternal peripheral blood sample is taken by venesection at about ten weeks gestation.[18]
Separation of cffDNA[edit]
Blood plasma is separated from the maternal blood sample using a laboratory centrifuge. The cffDNA is then isolated and purified.[19] In 2007, a standardized protocol for doing this was written by Legler et al through an evaluation of the scientific literature. The highest yield in cffDNA extraction was obtained with the "QIAamp DSP Virus Kit".[20]
Addition of formaldehyde to maternal blood samples increases the yield of cffDNA. Formaldehyde stabilizes intact cells, and therefore inhibits the further release of maternal DNA. With the addition of formaldehyde, the percentage of cffDNA recovered from a maternal blood sample varies between 0.32 percent and 40 percent with a mean of 7.7 percent.[21] Without the addition of formaldehyde, the mean percentage of cffDNA recovered has been measured at 20.2 percent. However, other figures vary between 5 and 96 percent.[22][23]
Recovery of cffDNA may be related to the length of the DNA fragments. Another way to increase the fetal DNA is based on physical length of DNA fragments. Smaller fragments can represent up to seventy percent of the total cell free DNA in the maternal blood sample.
Analysis of cffDNA[edit]
In real-time PCR, fluorescent probes are used to monitor the accumulation of amplicons. The reporter fluorescent signal is proportional to the number of amplicons generated. The most appropriate real time PCR protocol is designed according to the particular mutation or genotype to be detected. Point mutations are analysed with qualitative real time PCR with the use of allele specific probes. insertions and deletions are analyzed by dosage measurements using quantitative real time PCR.
cffDNA may be detected by finding paternally inherited DNA sequences via polymerase chain reaction (PCR).[24]>[25]
Quantitative real-time PCR[edit]
In 2010, Hill et al analyzed the sex-determining region Y gene (SRY) and the Y chromosome short tandem repeat "DYS14" in cffDNA from 511 pregnancies using a quantitative real-time PCR (RT-qPCR). In 401 of 403 pregnancies where maternal blood was drawn at seven weeks gestation or more, both segments of DNA were found.[26]
Nested PCR[edit]
In 2001, Al-Yatama et al evaluated the use of nested polymerase chain reaction (nested PCR) to determine sex by detecting a Y chromosome specific signal in the cffDNA from maternal plasma. Nested PCR detected 53 of 55 male fetuses. The cffDNA from the plasma of 3 of 25 women with female fetuses contained the Y chromosome-specific signal. The sensitivity of nested PCR in this experiment was 96 percent. The specificity was 88 percent.[27]
Digital PCR[edit]
Microfluidic devices allow the quantification of cffDNA segments in maternal plasma with accuracy beyond that of real-time PCR. Point mutations, loss of heterozygosity and aneuploidy can be detected in a single PCR step.[28][29][30] Digital PCR can differentiate between maternal blood plasma and fetal DNA in a multiplex fashion.[28]
Shotgun sequencing[edit]
High throughput shotgun sequencing using tools such as Solexa or Illumina, yields approximately 5 million sequence tags per sample of maternal serum. In 2008, Fan et al identified aneuploid pregnancies such as trisomy when testing at the fourteenth week of gestation. In 2010, fetal whole of genome mapping by parental haplotype analysis was completed using sequencing of cffDNA from maternal serum.[13] Chiu et al. in 2010 studied 753 pregnant females, using a 2-plex massively parallel maternal plasma DNA sequencing and trisomy was diagnosed with z-score greater than 3.[31] The sequencing gave sensitivity of 100 percent, specificity of 97.9 percent, a positive predictive value of 96.6 percent and a negative predictive value of 100 percent.
Mass spectrometry[edit]
Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) combined with single-base extension after PCR allows cffDNA detection with single base specificity and single DNA molecule sensitivity.[32] DNA is amplified by PCR. Then, linear amplification with base extension reaction (with a third primer) is designed to anneal to the region upstream from the mutation site. One or two bases are added to the extension primer to produce two extension products from wild-type DNA and mutant DNA. Single base specificity provides advantages over hybridization-based techniques using TaqMan hydrolysis probes. In 2008, when assessing the technique, Ding et al found no false positives or negatives when looking for cffDNA to determine fetal sex in sixteen maternal plasma samples.[32] In 2010, Akolekar et al correctly detected the sex of ninety of ninety-one male foetuses using MALDI-TOF mas spectrometry. The technique had accuracy, sensitivity and specificity of over 99 percent.[33]
Epigenetic modifications[edit]
Differences in gene activation between maternal and fetal DNA can be exploited. epigenetic modifications (heritable modifications that change gene function without changing DNA sequence) can be used to detect cffDNA.[34][35] The hypermethylated RASSF1A promoter is a universal fetal marker used to confirm the presence of cffDNA.[36] In 2012, White et al described a technique where cffDNA was extracted from maternal plasma and then digested with methylation-sensitive and insensitive restriction enzymes. Then, real-time PCR analysis of RASSF1A, SRY, and DYS14 was done.[36] The procedure detected 79 out of 90 (88 percent) maternal blood samples where hypermethylated RASSF1A was present.
mRNA[edit]
mRNA transcripts from genes expressed in the placenta are detectable in maternal plasma.[37] In this procedure, plasma is centrifuged so an aqueous layer appears. This layer is transferred and from it RNA is extracted. RT-PCR is used to detect a selected expression of RNA. For example, Human placental lactogen (hPL) and beta-hCG mRNA are stable in maternal plasma and can be detected. (Ng et al. 2002). This can help to confirm the presence of cffDNA in maternal plasma.[16]
Applications[edit]
Prenatal sex determination[edit]
X-linked genetic disorder
The analysis of cffDNA from a sample of maternal plasma allows the determination of fetal sex. Whether the sex of the fetus is male or female allows the determination of the risk of a particular X-linked recessive genetic disorder in a particular pregnancy, especially where the mother is a genetic carrier of the disorder.[38] Most X-linked diseases are evident in males because of the lack of the second X-chromosome that can compensate for the disease allele. Common X-linked recessive disorders include Duchenne muscular dystrophy, fragile X syndrome and haemophilia.
In comparison to obstetric ultrasonography which is unreliable for sex determination in the first trimester and amniocentesis which carries a small risk of miscarriage, sampling of maternal plasma for analysis of cffDNA is without risk.[39] The main targets in the cffDNA analysis are the gene responsible for the sex-determining region Y protein (SRY) on the Y chromosome and the DYS14 sequence.[40][41]
Congenital adrenal hyperplasia
In congenital adrenal hyperplasia, the adrenal cortex lacks appropriate corticosteroid synthesis, leading to excess adrenal androgens and affects female fetuses.[42] There is an external masculinization of the genitalia in the female fetuses.[43] Mothers of at risk fetuses are given dexamethasone at 6 weeks gestation to suppress pituitary gland release of androgens.[44]
If analysis of cffDNA obtained from a sample of maternal plasma lacks genetic markers found only on the Y chromosome, it is suggestive of a female fetus. However, it might also indicate a failure of the analysis itself ( a false negative result). Paternal genetic polymorphisms and sex-independent markers may be used to detect cffDNA. An high degree of heterozygosity of these markers must be present for this application.[45]
Paternity testing
Prenatal DNA paternity testing is commercially available. The test can be performed at nine weeks gestation.[citation needed]
Single gene disorders[edit]
Autosomal dominant and recessive single gene disorders which have been diagnosed prenatally by analysing paternally inherited DNA include cystic fibrosis, beta thalassemia, sickle cell anemia, spinal muscular atrophy, and myotonic dystrophy.[24][40] Prenatal diagnosis of single gene disorders which are due to an autosomal recessive mutation, a maternally inherited autosomal dominant mutation or large sequence mutations that include duplication, expansion or insertion of DNA sequences is more difficult.[46]
In cffDNA, fragments of 200 – 300 bp length involved in single gene disorders are more difficult to detect.
For example, the autosomal dominant condition, achondroplasia is caused by the FGFR3 gene point mutation.[47] In 2007, a study of two pregnancies with a fetus with achondroplasia found a paternally inherited G1138A mutation from cffDNA from a maternal plasma sample in one and a G1138A de novo mutation from the other.[47]
In studies of the genetics of Huntington's chorea using qRT-PCR of cffDNA from maternal plasma samples, CAG repeats have been detected at normal levels (17, 20 and 24).[48]
cffDNA may also be used to diagnose single gene disorders.[15]Developments in laboratory processes using cffDNA may allow prenatal diagnosis of aneuploidies such as trisomy 21 (Down's syndrome) in the fetus.[49][29]
Hemolytic disease of the fetus and newborn[edit]
Incompatibility of fetal and maternal RhD antigens is the main cause of Hemolytic disease of the newborn.[50] Approximately 15 percent of Caucasian women, 3 to 5 percent of black Africa women and less than 3 percent of Asian women are RhD negative.[51]
Accurate prenatal diagnosis is important because the disease can be fatal to the newborn and because treatment including intramuscular immunoglobulin (Anti-D) or intravenous immunoglobulin can be administered to mothers at risk.[52]
In 2010, Cardo et al reported that PCR to detect RHD (gene) gene exons 5 and 7 from cffDNA obtained from maternal plasma between 9 and 13 weeks gestation gave a high degree of specificity, sensitivity and diagnostic accuracy (>90 percent) when compared to RhD determination from newborn cord blood serum.[50] In 2013, Aykute et al found similar results targeting exons 7 and 10.[53] In 2015, Svobodova et al reported that droplet digital PCR in fetal RhD determination was comparable to a routine real-time PCR technique.[54]
Routine determination of fetal RhD status from cffDNA in maternal serum allows early management of at risk pregnancies while decreasing unnecessary use of Anti-D by over 25 percent.[55]
Aneuploidy[edit]
Sex chromosomes
Analysis of maternal serum cffDNA by high-throughput sequencing can detect common fetal sex chromosome aneuploidies such as Turner's syndrome, Klinefelter's syndrome and triple X syndrome but the procedure's positive predictive value is low.[56]
Trisomy 21
Fetal trisomy of chromosome 21 is the cause of Down's syndrome. This trisomy can be detected by analysis of cffDNA from maternal blood by massively parallel shotgun sequencing (MPSS).[57] Another technique is digital analysis of selected regions (DANSR).[57] However, such tests show inconsistent degrees of sensitivity and specificity and therefore may be best used to confirm a positive maternal screening test such as ultrasound markers of the condition.[57].[58]
Trisomy 13 and 18
Analysis of cffDNA from maternal plasma with MPSS looking for trisomy 13 or 18 is possible[59]
Factors limiting sensitivity and specificity include the levels of cffDNA in the maternal plasma; maternal chromosomes may have mosaicism.[60]
A number of fetal nucleic acid molecules derived from aneuploid chromosomes can be detected including SERPINEB2 mRNA, clad B, hypomethylated SERPINB5 from chromosome 18, placenta-specific 4 (PLAC4), hypermethylated holocarboxylase synthetase (HLCS) and c21orf105 mRNA from chromosome 12.[61] With complete trisomy, the mRNA alleles in maternal plasma isn't the normal 1:1 ratio, but is in fact 2:1. Allelic ratios determined by epigenetic markers can also be used to detect the complete trisomies. Massive parallel sequencing and digital PCR for fetal aneuploidy detection can be used without restriction to fetal-specific nucleic acid molecules. (MPSS) is estimated to have a sensitivity of between 96 and 100%, and a specificity between 94 and 100% for detecting Down syndromeIt can be performed at 10 weeks of gestational age.[62] One study in the United States estimated a false positive rate of 0.3% and a positive predictive value of 80% when using cffDNA to detect Down syndrome.[63]
Preeclampsia[edit]
Preeclampsia is a complex condition of pregnancy involving hypertension and proteinuria usually after 20 weeks gestation.[64] It is associated with poor cytotrophoblastic invasion of the myometrium. Onset of the condition between 20 and 34 weeks gestation, is considered "early".[65] Maternal plasma samples in pregnancies complicated by preeclampsia have significantly higher levels of cffDNA that those in normal pregnancies.[66][67][68] This holds true for early onset preeclampsia.[65]
Future perspectives[edit]
New generation sequencing may be used to yield a whole genome sequence from cffDNA. This raises ethical questions.[69] However, the utility of the procedure may increase as clear associations between specific genetic variants and disease states are discovered.[70][71]
See also[edit]
Triple test
Quad test
References[edit]
Jump up ^ Alberry, M., et al. (2007). "Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast". Prenatal Diagnosis 27 (5): 415-418.
Jump up ^ Gupta, A. K., et al. (2004). "Detection of fetal DNA and RNA in placenta-derived syncytiotrophoblast microparticles generated in vitro". Clinical Chemistry 50 (11): 2187-2190.
Jump up ^ Smets, E. M.; Visser, A.; Go, A. T.; van Vugt, J. M.; Oudejans, C. B. (2006). "Novel biomarkers in preeclampsia". Clinica Chimica Acta: International Journal of Clinical Chemistry 364 (1-2): 22-32.
Jump up ^ Chan, K. C., et al. (2004). "Size distributions of maternal and fetal DNA in maternal plasma". Clinical Chemistry 50 (1): 88-92.
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^ Jump up to: a b Wright, C. F.; Burton, H. (2009). "The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis". Human Reproduction Update 15 (1): 139-151.
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^ Jump up to: a b Traeger-Synodinos, J. (2006). "Real-time PCR for prenatal and preimplantation genetic diagnosis of monogenic diseases". Molecular Aspects of Medicine 27 (2-3): 176-191.
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^ Jump up to: a b Zimmermann, B. G., et al. (2008). "Digital PCR: a powerful new tool for noninvasive prenatal diagnosis?". Prenatal Diagnosis 28 (12): 1087-1093.
^ Jump up to: a b Lo, Y. M., et al. (2007). "Digital PCR for the molecular detection of fetal chromosomal aneuploidy". Proceedings of the National Academy of Sciences of the United States of America 104 (32): 13116-13121.
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^ Jump up to: a b Ding, C. (2008). "Maldi-TOF mass spectrometry for analyzing cell-free fetal DNA in maternal plasma". Methods in Molecular Biology 444: 253-267.
Jump up ^ Akolekar, R.; Farkas, D. H.; VanAgtmael, A. L.; Bombard, A. T.; Nicolaides, K. H. (2010). "Fetal sex determination using circulating cell-free fetal DNA (ccffDNA) at 11 to 13 weeks of gestation". Prenatal Diagnosis 30 (10): 918-923.
Jump up ^ Tong, Y. K.; Chiu, R. W.; Chan, K. C.; Leung, T. Y.; Lo, Y. M. (2012). "Technical concerns about immunoprecipitation of methylated fetal DNA for noninvasive trisomy 21 diagnosis". Nature Medicine 18 (9): 1327-1328; author reply 1328-1329.
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^ Jump up to: a b White, H. E., Dent, C. L.; Hall, V. J.; Crolla, J. A.; Chitty, L. S. (2012). "Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis". PLoS ONE 7 (9): e45073.
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^ Jump up to: a b Bustamante-Aragones, A.; Gonzalez-Gonzalez, C.; de Alba, M. R.; Ainse, E.; Ramos, C. (2010). "Noninvasive prenatal diagnosis using ccffDNA in maternal blood: state of the art". Expert Review of Molecular Diagnostics 10 (2): 197-205.
Jump up ^ Zimmermann, B.; El-Sheikhah, A.; Nicolaides, K.; Holzgreve, W.; Hahn, S. (2005). "Optimized real-time quantitative PCR measurement of male fetal DNA in maternal plasma". Clinical Chemistry 51 (9): 1598-1604.
Jump up ^ Finning, K. M.; Chitty, L. S. (2008). "Non-invasive fetal sex determination: impact on clinical practice". Seminars in Fetal & Neonatal Medicine 13 (2): 69-75.
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Jump up ^ Sayres, L. C.; Cho, M. K. (2011). "Cell-free fetal nucleic acid testing: a review of the technology and its applications". Obstetrical & Gynecological Survey 66 (7): 431-442.
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^ Jump up to: a b Li, Y.; Page-Christiaens, G. C.; Gille, J. J.; Holzgreve, W.; Hahn, S. (2007). "Non-invasive prenatal detection of achondroplasia in size-fractionated cell-free DNA by MALDI-TOF MS assay". Prenatal Diagnosis 27 (1): 11-17.
Jump up ^ [2] De Die-Smulders, C. E. M.; De Wert, G. M. W. R.; Liebaers, I.; Tibben, A.; Evers-Kiebooms, G. (2013). "Reproductive options for prospective parents in families with Huntington's disease: Clinical, psychological and ethical reflections". Human Reproduction Update. 19 (3): 304–315. doi:10.1093/humupd/dms058. PMID 23377865.
Jump up ^ Fan, H. C.; Blumenfeld, Y. J.; Chitkara, U.; Hudgins, L.; Quake, S. R. (2008). "Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood". Proceedings of the National Academy of Sciences of the United States of America 105 (42): 16266-16271.
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Jump up ^ Okwundu C. and Afolabi B. "Intramuscular versus intravenous anti-D for preventing Rhesus alloimmunization during pregnancy." Cochrane Database Syst Rev. 2013 Jan 31;(1):CD007885. doi: 10.1002/14651858.CD007885.pub2
Jump up ^ Ayket A et al "Determination of fetal rhesus d status by maternal plasma DNA analysis" Balkan J Med Genet. 2013 Dec;16(2):33-8. doi: 10.2478/bjmg-2013-0029.
Jump up ^ Svobodova I. et al "Performance of Droplet Digital PCR in Non-Invasive Fetal RHD Genotyping - Comparison with a Routine Real-Time PCR Based Approach." PLoS One. 2015 Nov 12;10(11):e0142572. doi: 10.1371/journal.pone.0142572. eCollection 2015.
Jump up ^ Papasavva T. et al "Prevalence of RhD status and clinical application of non-invasive prenatal determination of fetal RHD in maternal plasma: a 5 year experience in Cyprus." BMC Res Notes. 2016 Apr 1;9:198. doi: 10.1186/s13104-016-2002-x.
Jump up ^ Zhang B. et al "Noninvasive prenatal screening for fetal common sex chromosome aneuploidies from maternal blood." J Int Med Res. 2017 Apr;45(2):621-630. doi: 10.1177/0300060517695008. Epub 2017 Mar 30.
^ Jump up to: a b c "Down Syndrome: Current Status, Challenges and Future Perspectives." Int J Mol Cell Med. 2016 Summer; 5(3): 125–133. PMCID: PMC5125364
Jump up ^ Mersy, E.; Smits, L. J. M.; Van Winden, L. A. A. P.; De Die-Smulders, C. E. M.; Paulussen, A. D. C.; MacVille, M. V. E.; Coumans, A. B. C.; Frints, S. G. M. (2013). "Noninvasive detection of fetal trisomy 21: Systematic review and report of quality and outcomes of diagnostic accuracy studies performed between 1997 and 2012". Human Reproduction Update. 19 (4): 318–29. doi:10.1093/humupd/dmt001. PMID 23396607.
Jump up ^ Clark-Ganhart C.A. et al "Understanding the Limitations of Circulating Cell Free Fetal DNA: An Example of Two Unique Cases." J Clin Gynecol Obstet. 2014 May;3(2):38-70.
Jump up ^ Wataganara, T., et al. (2003). "Maternal serum cell-free fetal DNA levels are increased in cases of trisomy 13 but not trisomy 18". Human Genetics 112 (2): 204-208.
Jump up ^ Chiu, R. W.; Lo, Y. M. (2011). "Non-invasive prenatal diagnosis by fetal nucleic acid analysis in maternal plasma: the coming of age". Seminars in Fetal & Neonatal Medicine 16 (2): 88-93.
Jump up ^ Noninvasive Prenatal Diagnosis of Fetal Aneuploidy Using Cell-Free Fetal Nucleic Acids in Maternal Blood: Clinical Policy (Effective 05/01/2013) from Oxford Health Plans
Jump up ^ Bianchi, D. W.; Parker, R. L.; Wentworth, J.; Madankumar, R.; Saffer, C.; Das, A. F.; Craig, J. A.; Chudova, D. I.; Devers, P. L.; Jones, K. W.; Oliver, K.; Rava, R. P.; Sehnert, A. J. (2014). "DNA Sequencing versus Standard Prenatal Aneuploidy Screening". New England Journal of Medicine. 370 (9): 799–808. doi:10.1056/NEJMoa1311037. PMID 24571752. . A recent study in the New England Journal of Medicine demonstrated the feasibility of using NIPT in a low risk population.
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Jump up ^ Yurkiewicz, I. R.; Korf, B. R.; Lehmann, L. S. (2014). "Prenatal whole-genome sequencing--is the quest to know a fetus's future ethical?". New England Journal of Medicine. 370 (3): 195–7. doi:10.1056/NEJMp1215536. PMID 24428465.
Jump up ^ Wellcome Trust Case Control Consortium; Clayton, David G.; Cardon, Lon R.; Craddock, Nick; Deloukas, Panos; Duncanson, Audrey; Kwiatkowski, Dominic P.; McCarthy, Mark I.; Ouwehand, Willem H.; Samani, Nilesh J.; Todd; Donnelly, Peter; Barrett, Jeffrey C.; Burton, Paul R.; Davison, Dan; Donnelly, Peter; Easton, Doug; Evans, David; Leung, Hin-Tak; Marchini, Jonathan L.; Morris; Spencer, Chris C. A.; Tobin, Martin D.; Cardon, Lon R.; Clayton, David G.; Attwood, Antony P.; Boorman, James P.; Cant, Barbara; Everson, Ursula; Hussey, Judith M. (June 2007). "Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls". Nature. 447 (7145): 661–78. Bibcode:2007Natur.447..661B. doi:10.1038/nature05911. PMC 2719288  . PMID 17554300.
Jump up ^ Mailman MD; Feolo M; Jin Y; Kimura M; Tryka K; Bagoutdinov R; Hao L; Kiang A; Paschall J; Phan L; Popova N; Pretel S; Ziyabari L; Lee M; Shao Y; Wang ZY; Sirotkin K; Ward M; Kholodov M; Zbicz K; Beck J; Kimelman M; Shevelev S; Preuss D; Yaschenko E; Graeff A; Ostell J; Sherry ST (October 2007). "The NCBI dbGaP database of genotypes and phenotypes". Nat. Genet. 39 (10): 1181–6. doi:10.1038/ng1007-1181. PMC 2031016  . PMID 17898773.
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