Joel Tomkins will make his England debut at outside centre in Saturday's first autumn Test against Australia.
Tomkins, 26, whose brother Sam will play for England in their Rugby League World Cup match against Ireland on the same day, partners Billy Twelvetrees in a new-look midfield at Twickenham.
Northampton's Lee Dickson is chosen at scrum-half ahead of Leicester's Ben Youngs, who is on the bench.
Billy Vunipola starts his first Test, and wing Marland Yarde his second.
Tomkins, who switched codes in 2011, said playing for England was the target he set himself when he moved from Wigan to Saracens.
"That was one of the main goals, to play international rugby. I never put a timescale on it but two years is relatively quickly I suppose," he told BBC Radio 5 live.
"I feel ready, I feel prepared for the game and I'm excited now about Saturday. Playing in front of 80,000 at Twickenham must be a massive buzz and one I'm looking forward to.
"Then, ultimately, I want to play in the World Cup. The World Cup is definitely a big goal of mine."
Number eight Vunipola, 20, will make his full debut after winning his first two caps from the bench on the summer tour against Argentina.
He will play for England alongside elder brother Mako, 22, who starts at loose-head prop, for the first time.
In the absence of Geoff Parling, who suffered a mild concussion during training, the in-form Courtney Lawes returns to the starting XV alongside Joe Launchbury in the second row.
Parling is one of five British & Irish Lions unavailable to England, joining flanker Tom Croft, prop Alex Corbisiero and centres Manu Tuilagi and Brad Barritt (a Lions replacement in Australia) on the injured list.
With Tuilagi and Barritt unavailable, Tomkins gets a chance to show his progress after switching codes from rugby league two years ago to join Saracens.
"Joel is ready for his chance," said England coach Stuart Lancaster.
"He has played in many high-profile games in his career and has a great temperament for the big occasion.
"Billy Vunipola and Marland Yarde made a big impression in Argentina and it's going to be a special occasion for them to run out at Twickenham in front of 82,000 passionate supporters for the first time."
Dickson, 28, started three matches in the 2012 Six Nations but subsequently played second fiddle to Youngs and Danny Care last season.
But with Youngs touring with the Lions and Care rested for the summer trip to Argentina, Dickson started both Tests and retains the number nine shirt after a strong start to the season.
The Wallabies are looking for a second successive win at Twickenham after a 20-14 success in south-west London 12 months ago.
"We are looking forward to the challenge of playing Australia," added Lancaster. "They have made great strides under Ewen McKenzie and their new coaching team and they are formidable opponents."
England team: Mike Brown (Harlequins), Chris Ashton (Saracens), Joel Tomkins (Saracens), Billy Twelvetrees (Gloucester), Marland Yarde (London Irish), Owen Farrell (Saracens), Lee Dickson (Northampton); Mako Vunipola (Saracens), Tom Youngs (Leicester), Dan Cole (Leicester), Joe Launchbury (Wasps), Courtney Lawes (Northampton), Tom Wood (Northampton), Chris Robshaw (captain, Harlequins), Billy Vunipola (Saracens).
Replacements: Dylan Hartley (Northampton), Joe Marler Harlequins), David Wilson (Bath), Dave Attwood Bath), Ben Morgan (Gloucester), Ben Youngs (Leicester), Toby Flood (Leicester), Ben Foden (Northampton).